Compounds for therapeutic use

ABSTRACT

Chemical entities of Formula (I): 
                         
Including enantiomers thereof, wherein R 1  has any of the values described herein, and compositions comprising such chemical entities; their preparation; and their use in various methods, including the treatment of depression, pain, cognitive disorders, neurodegenerative disorders, and other neurological and peripheral disorders.

RELATED APPLICATIONS

Any and all priority claims identified in the Application Data Sheet, orany correction thereto, are hereby incorporated by reference under 37CFR 1.57. For example, this application is a divisional of U.S. patentapplication Ser. No. 15/253,645, filed Aug. 31, 2016, the disclosure ofwhich is incorporated herein by reference in its entirety.

FIELD OF THE DISCLOSURE

This disclosure relates to chemical entities, including compounds, asdescribed herein; compositions containing them; methods of making them;and their use in various methods, including the treatment of depression,pain, dementia, and other neurological and peripheral disorders.

BACKGROUND

Discovered more than 50 years ago, ketamine is an anesthetic that isthought to act primarily by antagonizing the glutamatergic NMDAR(N-methyl-D-aspartate receptor). It is typically administeredintramuscularly or intravenously for starting and maintaining generalanesthesia in humans and other animals, and has also been used foranti-anxiety, sedation, and analgesic purposes. See, e.g., Costi et al.,Curr. Behay. Neurosci. Rep. 2015, 4. 216-225; Oddo et al., Crit. Care2016, 20, 128-138. In addition, ketamine has shown potent efficacy intreating depression and pain when administered at sub-anesthetic doses;even single infusions of such doses appear to show rapid action intreating bipolar depression and treatment-resistant major depression.Iadarola et al., Ther. Adv. Chronic Dis. 2015, 6, 97-114; Zarate et al.,Arch. Gen. Psychiatry 2006, 63, 856-864; Lally et al. Transl. Psychiatry2014, 4, e469; Murrough et al., Am. J. Psychiatry 2013, 170, 1134-1142.

Clinical use of ketamine is limited, however, by its poor oralbioavailability, abuse liability, and undesirable psychologicalreactions, such as dissociative effects and hallucinations observed ateven low doses. See, e.g., Strayer and Nelson, Am. J. Emerg. Med. 2008,26, 985-1028; Morgan and Curran, Addiction 2010, 107, 27-38. Inaddition, ketamine action is complicated by multiple metabolites arisingafter its administration, many of which do not have anestheticproperties. See, e.g., Leung et al., J. Med. Chem. 1986, 29, 2396-2399.

Recent studies have shown that a ketamine metabolite,(2R,6R)-hydroxynorketamine, has antidepressant activity in mice. Zanoset al., Nature 2016, 533, 481-486. In addition, hydroxynorketamine (HNK)metabolites have been implicated in the analgesic efficacy of ketaminein treating pain. Moaddel et al., Talanta 2010, 15, 1892-1904. Incontrast to ketamine, HNK is not known to inhibit NMDAR, but is thoughtto modulate a different glutamate receptor, the AMPA(α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor.Furthermore, the action of HNK does not appear to be associated withundesired effects that can result from ketamine therapy, such as abuseliability and anesthetic effects.

These observations highlight the need for alternative ketaminetherapeutics useful in treating depression, pain, and other CNSdisorders. The present disclosure meets these and other needs in the artby disclosing chemical entities, including compounds, which can actthrough HNK-mediated pathways.

SUMMARY

Disclosed are chemical entities of Formula (I):

including the various stereoisomers and enantiomers, wherein R¹ is asdescribed herein. Also disclosed are compositions comprising thecompounds of Formula (I); methods of making the compounds andcompositions; and their use in a wide range of methods that includetreating pain, depression, and other neurological disorders, as well asenhancing cognitive function.

DETAILED DESCRIPTION

The embodiments may be more fully appreciated by reference to thefollowing description, including the examples. Unless otherwise defined,all technical and scientific terms used herein have the same meaning ascommonly understood by one of ordinary skill in the art. Althoughmethods and materials similar or equivalent to those described hereincan be used in the practice or testing of the present embodiments,suitable methods and materials are described herein. In addition, thematerials, methods, and examples are illustrative only and not intendedto be limiting.

For the sake of brevity, all publications, including patentapplications, patents, and other citations mentioned herein, areincorporated by reference in their entirety. Citation of any suchpublication, however, shall not be construed as an admission that it isprior art.

Abbreviations

The specification includes numerous abbreviations, whose meanings arelisted in the following Table:

Abbreviation Definition AcCl Acetyl Chloride ACN Acetonitrile BSTFAN,O-Bis(trimethylsilyl)trifluoroacetamide CELITE ® Diatomaceous earthDBN 1,5-Diazabicyclo[4.3.0]non-5-ene DBU1,8-diazabicyclo[5.4.0]undec-7-ene DCM Dichloromethane DIPEA, DIEAN,N-ethyl-diisopropylamine or N,N- Diisopropyl-ethyl amine DMAN,N-Dimethylacetamide DMF N,N-Dimethylformamide DMSO DimethylsulfoxideEtOAc, or EA Ethyl acetate EtOH Ethanol Et₂O Diethyl ether HATU1-[Bis(dimethylamino)methylene]-1H- 1,2,3-triazolo[4,5-b] HBrHydrobromic acid HCl Hydrochloric acid HPLC High-performance liquidchromatography LCMS, LC/MS Liquid chromatography-mass spectrometryLiHMDS, LHMDS Lithium bis(trimethylsilyl)amide LDA Lithiumdiisopropylamide mCPBA meta-Chloroperoxybenzoic acid MeOH Methanol TMSClor Me₃SiCl Trimethylsilyl chloride TMSI or Me₃SiI Trimethylsilyl iodideMgSO₄ Magnesium sulfate Na₂CO₃ Sodium carbonate NaHCO₃ Sodiumbicarbonate NaOH Sodium hydroxide Na₂SO₃ Sodium sulfite Na₂SO₄ Sodiumsulfate NIS N-Iodosuccinimide i-PrOH Isopropanol i-Pr₂O Diisopropylether SiO₂ Silica TEA, Et₃N Triethylamine TFA Trifluoroacetic acid THFTetrahydrofuran

Terms and Definitions

The use of headings and subheadings provided in the sections of thisspecification is solely for convenience of reference and does not limitthe various embodiments herein, which are to be construed by referenceto the specification as a whole.

General

As used herein, the term “about” or “approximately” means within anacceptable range for a particular value as determined by one skilled inthe art, and may depend in part on how the value is measured ordetermined, e.g., the limitations of the measurement system ortechnique. For example, “about” can mean a range of up to 20%, up to10%, up to 5%, or up to 1% or less on either side of a given value.Alternatively, with respect to biological systems or processes, the term“about” can mean within an order of magnitude, within 5-fold, or within2-fold on either side of a value. Numerical quantities given herein areapproximate unless stated otherwise, meaning that the term “about” or“approximately” can be inferred when not expressly stated.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that, whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation of such given valuethat would reasonably be inferred based on the ordinary skill in theart, including equivalents and approximations due to the experimental ormeasurement conditions for such given value. Whenever a yield is givenas a percentage, such yield refers to a mass of the entity for which theyield is given with respect to the maximum amount of the same entity forwhich that could be obtained under the particular stoichiometricconditions. Concentrations that are given as percentages refer to massratios, unless indicated differently.

As used herein, the terms “a,” “an,” and “the” are to be understood asmeaning both singular and plural, unless explicitly stated otherwise.Thus, “a,” “an,” and “the” (and grammatical variations thereof whereappropriate) refer to one or more.

Furthermore, although items, elements or components of the embodimentsmay be described or claimed in the singular, the plural is contemplatedto be within the scope thereof, unless limitation to the singular isexplicitly stated.

The terms “comprising” and “including” are used herein in their open,non-limiting sense. Other terms and phrases used in this document, andvariations thereof, unless otherwise expressly stated, should beconstrued as open ended, as opposed to limiting. Thus, the term“example” is used to provide exemplary instances of the item indiscussion, not an exhaustive or limiting list thereof. Similarly,adjectives such as “conventional,” “traditional,” “normal,” “criterion,”“known,” and terms of similar meaning should not be construed aslimiting the item described to a given time period or to an itemavailable as of a given time, but instead should be read to encompassconventional, traditional, normal, or criterion technologies that may beavailable or known now or at any time in the future. Likewise, wherethis document refers to technologies that would be apparent or known toone of ordinary skill in the art, such technologies encompass thoseapparent or known to the skilled artisan now or at any time in thefuture.

The presence of broadening words and phrases such as “one or more,” “atleast,” “but not limited to,” or other like phrases in some instancesshould not be read to mean that the narrower case is intended orrequired in instances where such broadening phrases may be absent. Aswill become apparent to one of ordinary skill in the art after readingthis document, the illustrated embodiments and their variousalternatives may be implemented without confinement to the illustratedexamples.

Chemistry

The term “substituted,” as used herein, means that at least one hydrogenon the designated atom or group is replaced with a selection from theindicated group, provided that the designated atom's normal valence isnot exceeded. When a substituent is keto (i.e., ═O), then 2 hydrogenatoms on the atom are replaced.

A dash (“—”) that is not between two letters or symbols is used toindicate a point of covalent attachment for a substituent. For example,—(CH₂)C₃-C₇cycloalkyl is attached through carbon of the methylene (CH₂)group.

The term “alkyl” refers to a fully saturated aliphatic hydrocarbongroup. The alkyl moiety may be a straight- or branched-chain alkyl grouphaving from 1 to 12 carbon atoms in the chain. Examples of alkyl groupsinclude, but are not limited to, methyl (Me, which also may bestructurally depicted by the symbol, “-”), ethyl (Et), n-propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl,isopentyl, tert-pentyl, hexyl, isohexyl, and groups that in light of theordinary skill in the art and the teachings provided herein would beconsidered equivalent to any one of the foregoing examples. Alkyl groupsmay be optionally substituted with one or more substituents including,but not limited to, halo, hydroxyl, alkoxy, thioalkoxy, amino, andaminoalkyl.

The term “alkenyl” refers to optionally substituted unsaturatedaliphatic moieties having at least one carbon-carbon double bond andincluding E and Z isomers of said alkenyl moiety. Examples of alkenylradicals include ethenyl, propenyl, butenyl, 1,4-butadienyl,cyclopentenyl, cyclohexenyl and the like.

The term “alkynyl” refers to optionally substituted unsaturatedaliphatic moieties having at least one carbon-carbon triple bond andincludes straight and branched chain alkynyl groups. Examples of alkynylradicals include ethynyl, propynyl, butynyl and the like.

The term “haloalkyl” refers to a straight- or branched-chain alkyl grouphaving from 1 to 12 carbon atoms in the chain, substituting one or morehydrogens with halogens. Examples of haloalkyl groups include, but arenot limited to, —CF₃, —CHF₂, —CH₂F, —CH₂CF₃, —CH₂CHF₂, —CH₂CH₂F,—CH₂CH₂Cl, —CH₂CF₂CF₃ and other groups that in light of the ordinaryskill in the art and the teachings provided herein, would be consideredequivalent to any one of the foregoing examples.

The term “alkoxy” includes a straight chain or branched alkyl group withan oxygen atom linking the alkyl group to the rest of the molecule.Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy,pentoxy and so on. “Aminoalkyl,” “thioalkyl,” and “sulfonylalkyl” areanalogous to alkoxy, replacing the terminal oxygen atom of alkoxy with,respectively, NH (or NR), S (sulfur), and SO₂.

The term “haloalkoxy” refer to alkoxy groups substituting one or morehydrogens with halogens. Examples of haloalkoxy groups include, but arenot limited to, —OCF₃, —OCH₂CF₃, —OCH₂CHF₂, —OCH₂CH₂Cl, —OCH₂CF₂CF₃,—OCH(CH₃)CHF₂ and other groups that in light of the ordinary skill inthe art and the teachings provided herein, would be consideredequivalent to any one of the foregoing examples.

The term “amino” refers to the —NH₂ group.

The term “heteroatom” used herein refers to, for example, O (oxygen), S(sulfur),N (nitrogen), and Selenium (Se).

The term “aryl” refers to a monocyclic, or fused or spiro polycyclic,aromatic carbocycle (ring structure having ring atoms that are allcarbon), having from 3 to 12 ring atoms per ring (carbon atoms in arylgroups are sp2 hybridized). Illustrative examples of aryl groups includethe following moieties:

and the like.

The term “cycloalkyl” refers to a saturated or partially saturatedcarbocycle, such as monocyclic, fused polycyclic, bridged monocyclic,bridged polycyclic, spirocyclic, or spiro polycyclic carbocycle havingfrom 3 to 12 ring atoms per carbocycle. Where the term cycloalkyl isqualified by a specific characterization, such as monocyclic, fusedpolycyclic, bridged polycyclic, spirocyclic, and spiro polycyclic, thensuch term cycloalkyl refers only to the carbocycle so characterized.Illustrative examples of cycloalkyl groups include the followingentities, in the form of properly bonded moieties:

“Heterocycloalkyl” means a saturated cyclic group containing from 1 toabout 3 heteroatoms chosen from N, O, S, and Se with remaining ringatoms being carbon. Heterocycloalkyl groups have from 3 to about 8 ringatoms, and more typically have from 5 to 7 ring atoms. Examples ofheterocycloalkyl groups include morpholinyl, piperazinyl, piperidinyl,and pyrrolidinyl groups. A nitrogen in a heterocycloalkyl group mayoptionally be quaternized. A “heterocycloalkyl” refers to a monocyclic,or fused, bridged, or spiro polycyclic ring structure that is saturatedor partially saturated and has from 3 to 12 ring atoms per ringstructure selected from carbon atoms and up to three heteroatomsselected from nitrogen, oxygen, selenium, and sulfur. The ring structuremay optionally contain up to two oxo groups on carbon or sulfur ringmembers. Illustrative (but not limiting) entities, in the form ofproperly bonded moieties, include:

The term “heteroaryl” refers to a monocyclic, fused bicyclic, or fusedpolycyclic aromatic heterocycle (ring structure having ring atomsselected from carbon atoms and up to four heteroatoms selected fromnitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms perheterocycle. Illustrative examples of heteroaryl groups include thefollowing entities, in the form of properly bonded moieties:

Those skilled in the art will recognize that the species of cycloalkyl,aryl, heterocycloalkyl, and heteroaryl groups listed or illustratedabove are not exhaustive, and that additional species within the scopeof these defined terms may also be selected.

The term “halogen” represents chlorine, fluorine, bromine or iodine; andthe term “halo” represents chloro, fluoro, bromo or iodo.

The terms “optional” and “optionally” refer to the subsequentlydescribed event or circumstance and mean that it may or may not occur,and that the description includes instances where the event orcircumstance occurs and instances or circumstances where it does not.For example, “optionally substituted alkyl” encompasses both“unsubstituted alkyl” and “substituted alkyl” as defined below. It willbe understood by those skilled in the art, with respect to any groupcontaining one or more substituents, that such groups are not intendedto introduce any substitution or substitution patterns that aresterically impractical, synthetically non-feasible and/or inherentlyunstable.

Formulas

Certain compounds are described herein using a general formula thatincludes variables, e.g. R¹-R¹².

Any formula disclosed herein is intended to represent compounds havingstructures depicted by the structural formula as well as certainvariations or forms. In particular, compounds of any formula givenherein may have asymmetric centers and therefore exist in differentenantiomeric forms. All optical isomers and stereoisomers of thecompounds of the general formula, and mixtures thereof, are consideredwithin the scope of the formula. Thus, any formula given herein isintended to represent a racemate, one or more enantiomeric forms, one ormore diastereomeric forms, one or more atropisomeric forms, and mixturesthereof. Furthermore, certain structures may exist as geometric isomers(i.e., cis and trans isomers), as tautomers, or as atropisomers. Thesymbols are used as meaning the same spatial arrangement in chemicalstructures shown herein. Analogously, the symbols are used as meaningthe same spatial arrangement in chemical structures shown herein.

The term “chiral” refers to molecules, which have the property ofnon-superimposability of the mirror image partner.

“Stereoisomers” are compounds, which have identical chemicalconstitution, but differ with regard to the arrangement of the atoms orgroups in space.

A “diastereomer” is a stereoisomer with two or more centers of chiralityand whose molecules are not mirror images of one another. Diastereomershave different physical properties, e.g., melting points, boilingpoints, spectral properties, and reactivities. Mixtures of diastereomersmay separate under high resolution analytical procedures such aselectrophoresis, crystallization in the presence of a resolving agent,or chromatography, using, for example a chiral HPLC column.

“Enantiomers” refer to two stereoisomers of a compound, which arenon-superimposable mirror images of one another. A 50:50 mixture ofenantiomers is referred to as a racemic mixture or a racemate, which mayoccur where there has been no stereoselection or stereospecificity in achemical reaction or process.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., NewYork. Many organic compounds exist in optically active forms, i.e., theyhave the ability to rotate the plane of plane-polarized light. Indescribing an optically active compound, the prefixes D and L or R and Sare used to denote the absolute configuration of the molecule about itschiral center(s). The prefixes d and l or (+) and (−) are employed todesignate the sign of rotation of plane-polarized light by the compound,with (−) or l meaning that the compound is levorotatory. A compoundprefixed with (+) or d is dextrorotatory.

A “racemic mixture” or “racemate” is an equimolar (or 50:50) mixture oftwo enantiomeric species, devoid of optical activity. A racemic mixturemay occur where there has been no stereoselection or stereospecificityin a chemical reaction or process.

Chemical Entities

As used herein, the term “chemical entity” collectively refers to acompound, along with its salts, chelates, solvates, conformers,non-covalent complexes, metabolites, and prodrugs.

Compounds disclosed herein are described using standard nomenclature.Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which this disclosure belongs.

As used herein, a “compound” refers to any one of: (a) the actuallyrecited form of such compound; and (b) any of the forms of such compoundin the medium in which the compound is being considered when named. Forexample, reference herein to a compound such as R—COOH, encompassesreference to any one of, for example, R—COOH(s), R—COOH(sol), andR—COO-(sol). In this example, R—COOH(s) refers to the solid compound, asit could be for example in a tablet or some other solid pharmaceuticalcomposition or preparation; R—COOH(sol) refers to the un-dissociatedform of the compound in a solvent; and R—COO-(sol) refers to thedissociated form of the compound in a solvent, such as the dissociatedform of the compound in an aqueous environment, whether such dissociatedform derives from R—COOH, from a salt thereof, or from any other entitythat yields R—COO— upon dissociation in the medium being considered.

In another example, an expression such as “exposing an entity to acompound of formula R—COOH” refers to the exposure of such entity to theform, or forms, of the compound R—COOH that exists, or exist, in themedium in which such exposure takes place. In still another example, anexpression such as “reacting an entity with a compound of formulaR—COOH” refers to the reacting of (a) such entity in the chemicallyrelevant form, or forms, of such entity that exists, or exist, in themedium in which such reacting takes place, with (b) the chemicallyrelevant form, or forms, of the compound R—COOH that exists, or exist,in the medium in which such reacting takes place. In this regard, ifsuch entity is for example in an aqueous environment, it is understoodthat the compound R—COOH is in such same medium, and therefore theentity is being exposed to species such as R—COOH(aq) and/or R—COO-(aq),where the subscript “(aq)” stands for “aqueous” according to itsconventional meaning in chemistry and biochemistry. A carboxylic acidfunctional group has been chosen in these nomenclature examples; thischoice is not intended, however, as a limitation but it is merely anillustration. It is understood that analogous examples can be providedin terms of other functional groups, including but not limited tohydroxyl, basic nitrogen members, such as those in amines, and any othergroup that interacts or transforms according to known manners in themedium that contains the compound. Such interactions and transformationsinclude, but are not limited to, dissociation, association, tautomerism,solvolysis, including hydrolysis, solvation, including hydration,protonation and deprotonation. No further examples in this regard areprovided herein because these interactions and transformations in agiven medium are known by any one of ordinary skill in the art.

In another example, a “zwitterionic” compound is encompassed herein byreferring to a compound that is known to form a zwitterion, even if itis not explicitly named in its zwitterionic form. Terms such aszwitterion, zwitterions, and their synonyms zwitterionic compound(s) arestandard IUPAC-endorsed names that are well known and part of standardsets of defined scientific names. In this regard, the name zwitterion isassigned the name identification CHEBI:27369 by the Chemical Entities ofBiological Interest (ChEBI) dictionary of molecular entities. As isgenerally well known, a zwitterion or zwitterionic compound is a neutralcompound that has formal unit charges of opposite sign. Sometimes thesecompounds are referred to by the term “inner salts”. Other sources referto these compounds as “dipolar ions”, although the latter term isregarded by still other sources as a misnomer. As a specific example,aminoethanoic acid (the amino acid glycine) has the formula H₂NCH₂COOH,and it exists in some media (in this case in neutral media) in the formof the zwitterion+H₃NCH₂COO—. Zwitterions, zwitterionic compounds, innersalts, and dipolar ions in the known and well established meanings ofthese terms are within the scope of this invention, as would in any casebe so appreciated by those of ordinary skill in the art. Because thereis no need to name each and every embodiment that would be recognized bythose of ordinary skill in the art, no structures of the zwitterioniccompounds that are associated with the compounds of this invention aregiven explicitly herein. They are, however, part of the embodiments ofthis invention. No further examples in this regard are provided hereinbecause the interactions and transformations in a given medium that leadto the various forms of a given compound are known by any one ofordinary skill in the art.

Isotopes may be present in the compounds described. Each chemicalelement present in a compound either specifically or genericallydescribed herein may include any isotope of said element. Any formulagiven herein is also intended to represent unlabeled forms as well asisotopically labeled forms of the compounds. Isotopically labeledcompounds have structures depicted by the formulas given herein exceptthat one or more atoms are replaced by an atom having a selected atomicmass or mass number. Examples of isotopes that can be incorporated intocompounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine,such as ²H (deuterium), ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S,¹⁸F, ³⁶Cl, and ¹²⁵I, respectively.

When referring to any formula given herein, the selection of aparticular moiety from a list of possible species for a specifiedvariable is not intended to define the same choice of the species forthe variable appearing elsewhere. That is, where a variable appears morethan once, the choice of the species from a specified list isindependent of the choice of species for the same variable elsewhere inthe formula, unless otherwise stated.

By way of a first example on substituent terminology, if substituent S¹_(example) is one of S₁ and S₂, and substituent S² _(example) is one ofS₃ and S₄, then these assignments refer to embodiments of this inventiongiven according to the choices S¹ _(example) is S₁ and S² _(example) isS₃; S¹ _(example) is S₁ and S² _(example) is S₄; S¹ _(example) is S₂ andS² _(example) is S₃; S¹ _(example) is S₂ and S² _(example) is S₄; andequivalents of each one of such choices. The shorter terminology “S¹_(example) is one of S₁ and S₂ and “S² _(example) is one of S₃ and S₄ isaccordingly used herein for the sake of brevity but not by way oflimitation. The foregoing first example on substituent terminology,which is stated in generic terms, is meant to illustrate the varioussubstituent assignments described herein. The foregoing convention givenherein for substituents extends, when applicable, to members such as R¹,R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², and R¹³, and any othergeneric substituent symbol used herein.

Furthermore, when more than one assignment is given for any member orsubstituent, embodiments of this invention comprise the variousgroupings that can be made from the listed assignments, takenindependently, and equivalents thereof. By way of a second example onsubstituent terminology, if it is herein described that substituentS_(example) is one of S₁, S₂ and S₃, the listing refers to embodimentsof this invention for which S_(example) is S₁; S_(example) is S₂;S_(example) is S₃; S_(example) is one of S₁ and S₂; S_(example) is oneof S₁ and S₃; S_(example) is one of S₂ and S₃; S_(example) is one of S₁,S₂ and S₃; and S_(example) is any equivalent of each one of thesechoices. The shorter terminology “S_(example) is one of S₁, S₂ and S₃”is accordingly used herein for the sake of brevity, but not by way oflimitation. The foregoing second example on substituent terminology,which is stated in generic terms, is meant to illustrate the varioussubstituent assignments described herein. The foregoing convention givenherein for substituents extends, when applicable, to members such as R¹,R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², and R¹³, and any othergeneric substituent symbol used herein.

The nomenclature “C_(i-j)” with j>i, when applied herein to a class ofsubstituents, is meant to refer to embodiments of this invention forwhich each and every one of the number of carbon members, from i to jincluding i and j, is independently realized. By way of example, theterm C₁₋₃ refers independently to embodiments that have one carbonmember (C₁), embodiments that have two carbon members (C₂), andembodiments that have three carbon members (C₃).

The term C_(n-m)alkyl refers to an aliphatic chain, whether straight orbranched, with the total number N of carbon members in the chain thatsatisfies n≤N≤m, with m>n.

According to the foregoing interpretive considerations on assignmentsand nomenclature, it is understood that explicit reference herein to aset implies, where chemically meaningful and unless indicated otherwise,independent reference to embodiments of such set, and reference to eachand every one of the possible embodiments of subsets of the set referredto explicitly.

Compositions

The term “composition,” as in pharmaceutical composition, is intended toencompass a product comprising the active ingredient(s), and the inertingredient(s) (pharmaceutically acceptable excipients) that make up thecarrier, as well as any product which results, directly or indirectly,from combination, complexation, or aggregation of any two or more of theingredients, or from dissociation of one or more of the ingredients, orfrom other types of reactions or interactions of one or more of theingredients. Accordingly, the pharmaceutical compositions of the presentinvention encompass any composition made by admixing a compound ofFormula (I) and a pharmaceutically acceptable excipient.

The term “therapeutically effective amount” or “effective amount” meansan amount effective, when administered to a human or non-human patient,to provide any therapeutic benefit. A therapeutic benefit may be anamelioration of symptoms, e.g., an amount effective to decrease thesymptoms of a depressive disorder, cognitive disorder, or pain. Atherapeutically effective amount of a compound is also an amountsufficient to provide a significant positive effect on any indicia of adisease, disorder, or condition e.g. an amount sufficient tosignificantly reduce the frequency and severity of depressive symptomsor pain. A significant effect on an indicia of a disorder or conditionincludes a statistically significant in a standard parametric test ofstatistical significance such as Student's T-test, where p<0.05; thoughthe effect need not be significant in some embodiments.

A “pharmaceutical compositions” is a composition comprising at least oneactive agent, such as a compound, or pharmaceutically acceptable saltthereof, of Formula (I), and at least one other substance, such as acarrier, excipient, or diluent.

The term “carrier” applies to pharmaceutical compositions of thedisclosure and refers to a diluent, adjuvant, excipient, or vehicle withwhich an active compound is administered.

The term “pharmaceutically acceptable,” as used in connection withcompositions of the invention, refers to molecular entities and otheringredients of such compositions that are physiologically tolerable anddo not typically produce untoward reactions when administered to ananimal (e.g., human). The term “pharmaceutically acceptable” may alsomean approved by a regulatory agency of the Federal or a stategovernment or listed in the U.S. Pharmacopeia or other generallyrecognized pharmacopeia for use in animals (e.g. mammals), and moreparticularly in humans.

A “pharmaceutically acceptable excipient” refers to a substance that isnon-toxic, biologically tolerable, and otherwise biologically suitablefor administration to a subject, such as an inert substance, added to apharmacological composition or otherwise used as a vehicle, carrier, ordiluents to facilitate administration of an agent and that is compatibletherewith. Examples of excipients include calcium carbonate, calciumphosphate, various sugars and types of starch, cellulose derivatives,gelatin, vegetable oils, and polyethylene glycols. Suitablepharmaceutical carriers include those described in Remington: TheScience and Practice of Pharmacy, 21^(st) Ed., Lippincott Williams &Wilkins (2005).

A “pharmaceutically acceptable salt” is intended to mean a salt of afree acid or base of a compound represented by Formula (I) that isnon-toxic, biologically tolerable, or otherwise biologically suitablefor administration to the subject. See, generally, G. S. Paulekuhn etal., J. Med. Chem. 2007, 50, 6665-6672; Berge et al., J. Pharm. Sci.1977, 66, 1-19; Stahl and Wermuth (eds), Pharmaceutical Salts;Properties, Selection, and Use: 2nd Revised Edition, Wiley-VCS, Zurich,Switzerland (2011). Examples of pharmaceutically acceptable salts arethose that are pharmacologically effective and suitable for contact withthe tissues of patients without undue toxicity, irritation, or allergicresponse. A compound of Formula (I) may possess a sufficiently acidicgroup, a sufficiently basic group, or both types of functional groups,and accordingly react with a number of inorganic or organic bases, andinorganic and organic acids, to form a pharmaceutically acceptable saltbases, and inorganic and organic acids, to form a pharmaceuticallyacceptable salt.

The term “carrier” refers to an adjuvant, vehicle, or excipients, withwhich the compound is administered. In preferred embodiments of thisinvention, the carrier is a solid carrier. Suitable pharmaceuticalcarriers include those described in Remington: The Science and Practiceof Pharmacy, 21^(st) Ed., Lippincott Williams & Wilkins (2005).

The term “dosage form,” as used herein, is the form in which the dose isto be administered to the subject or patient. The drug is generallyadministered as part of a formulation that includes nonmedical agents.The dosage form has unique physical and pharmaceutical characteristics.Dosage forms, for example, may be solid, liquid or gaseous. “Dosageforms” may include for example, a capsule, tablet, caplet, gel caplet(gelcap), syrup, a liquid composition, a powder, a concentrated powder,a concentrated powder admixed with a liquid, a chewable form, aswallowable form, a dissolvable form, an effervescent, a granulatedform, and an oral liquid solution. In a specific embodiment, the dosageform is a solid dosage form, and more specifically, comprises a tabletor capsule.

As used herein, the term “inert” refer to any inactive ingredient of adescribed composition. The definition of “inactive ingredient” as usedherein follows that of the U.S. Food and Drug Administration, as definedin 21 C.F.R. 201.3(b)(8), which is any component of a drug product otherthan the active ingredient.

Methods and Uses

As used herein, the term “disorder” is used interchangeably with“disease” or “condition”. For example, a neurological disorder alsomeans a neurological disease or a neurological condition.

As used herein, the term “cognitive impairment” is used interchangeablywith “cognitive dysfunction” or “cognitive deficit,” all of which aredeemed to cover the same therapeutic indications.

The terms “treating,” “treatment,” and “treat” cover therapeutic methodsdirected to a disease-state in a subject and include: (i) preventing thedisease-state from occurring, in particular, when the subject ispredisposed to the disease-state but has not yet been diagnosed ashaving it; (ii) inhibiting the disease-state, e.g., arresting itsdevelopment (progression) or delaying its onset; and (iii) relieving thedisease-state, e.g., causing regression of the disease state until adesired endpoint is reached. Treating also includes ameliorating asymptom of a disease (e.g., reducing the pain, discomfort, or deficit),wherein such amelioration may be directly affecting the disease (e.g.,affecting the disease's cause, transmission, or expression) or notdirectly affecting the disease.

As used in the present disclosure, the term “effective amount” isinterchangeable with “therapeutically effective amount” and means anamount or dose of a compound or composition effective in treating theparticular disease, condition, or disorder disclosed herein, and thus“treating” includes producing a desired preventative, inhibitory,relieving, or ameliorative effect. In methods of treatment according tothe invention, “an effective amount” of at least one compound accordingto the invention is administered to a subject (e.g., a mammal). In someembodiments, an “effective amount” also means an amount or dose of acompound or composition effective to modulate an HNK-associatedsignaling pathway, such as a glutamatergic pathway. The “effectiveamount” will vary, depending on the compound, the disease, the type oftreatment desired, and its severity, and age, weight, of the subject,etc.

The term “animal” is interchangeable with “subject” and may be avertebrate, in particular, a mammal, and more particularly, a human, andincludes a laboratory animal in the context of a clinical trial orscreening or activity experiment. Thus, as can be readily understood byone of ordinary skill in the art, the compositions and methods of thepresent invention are particularly suited to administration to anyvertebrate, particularly a mammal, and more particularly, a human.Medical treatment can include treatment of an existing condition, suchas a disease or disorder, prophylactic or preventative treatment, ordiagnostic treatment. In some embodiments the patient is a humanpatient.

As used herein, a “control animal” or a “normal animal” is an animalthat is of the same species as, and otherwise comparable to (e.g.,similar age, sex), the animal that is trained under conditionssufficient to induce transcription-dependent memory formation in thatanimal.

A “patient” means any human or non-human animal in need of medicaltreatment. Medical treatment can include treatment of an existingcondition, such as a disease or disorder, prophylactic or preventativetreatment, or diagnostic treatment. In some embodiments the patient is ahuman patient.

“Administering” means introducing into the body of a subject a chemicalentity, such as a compound or pharmaceutically acceptable salt thereof,or a composition containing such a chemical entity, for use via anyappropriate route, for example, oral administration in either solid orliquid dosage form.

By “enhance,” “enhancing,” or “enhancement” is meant the ability topotentiate, increase, improve or make greater or better, relative tonormal, a biochemical or physiological action or effect. For example,enhancing long term memory formation refers to the ability to potentiateor increase long term memory formation in an animal relative to (or“compared to”) the normal long term memory formation of the animal orcontrols. As a result, long term memory acquisition is faster or betterretained. Enhancing performance of a cognitive task refers to theability to potentiate or improve performance of a specified cognitivetask by an animal relative to the normal performance of the cognitivetask by the animal or controls.

As used herein, the terms “training protocol,” or “training,” refer toeither “cognitive training” or “motor training.”

Reference will now be made to the embodiments of the present invention,examples of which are illustrated by and described in conjunction withthe accompanying drawings and examples. While certain embodiments aredescribed herein, it is understood that the described embodiments arenot intended to limit the scope of the invention. On the contrary, thepresent disclosure is intended to cover alternatives, modifications, andequivalents that can be included within the invention as defined by theappended claims.

Compounds and Chemical Entities

The disclosure relates to compounds and chemical entities of Formula(I), and their use in the disclosed methods.

In some embodiments, the disclosure provides a chemical entity ofFormula (I):

-   -   wherein:    -   R¹ is —H; or    -   R¹ is —C₁₋₆alkyl, optionally substituted with one or more        members, each independently selected from the group consisting        of: -halo, -hydroxy, -alkoxy, -amino and -carboxyl; or    -   R¹ is —C₃₋₈alkenyl or —C₃₋₈alkynyl, each optionally substituted        with one or more members, each independently selected from the        group consisting of: -halo, -hydroxy, —C₁₋₄ alkyl, —C₁₋₄ alkoxy,        and amino; or    -   R¹ is —(CH₂)_(n)aryl, —(CH₂)_(n)heteroaryl,        —(CH₂)_(n)cycloalkyl, or —(CH₂)_(n)heterocycloalkyl, each        optionally substituted with one or more members, each        independently selected from the group consisting of: -halo,        -hydroxy, —C₁₋₄ alkyl, —C₁₋₄ alkoxy, and -amino, wherein n is        independently an integer selected from 0, 1, 2, 3, and 4; or    -   R¹ is —COR², —CONR³R⁴, —CR⁵R⁶NR⁷R⁸, —CHR⁹R¹⁰, or —C(OH)R¹¹R¹²,    -   wherein R², R³, R⁴, R⁷ and R⁸ are each independently selected        from the group consisting of: —H, —C₁₋₈alkyl, and        —C₁₋₈haloalkyl;    -   R⁵ and R⁶ are each independently selected from the group        consisting of: —H, -halo, —NH₂, —C₁₋₈alkyl, —C₁₋₈haloalkyl,        —(CH₂)_(n)CONH₂, —(CH₂)_(n)COOH, —(CH₂)_(n)aryl,        —(CH₂)_(n)heteroaryl, —(CH₂)_(n)cycloalkyl, and        —(CH₂)_(n)heterocycloalkyl, each optionally substituted with one        or more members, each independently selected from the group        consisting of: -guanidyl, -urea, -halo, -alkyl, -hydroxy,        -amino, -alkoxy, -2,3-dihydro-1H-pyrrole-1-carboxamide,        —(CH₂)_(n)CONR^(1A)R^(1B), —(CH₂)_(n)NHC(═O)R^(1A),        —(CH₂)_(n)NR^(1A)R^(1B), —(CH₂)_(n)OR^(1C), —(CH₂)_(n)SR^(1C)        and —(CH₂)_(n)SeR^(1C), wherein n is independently an integer        selected from 0, 1, 2, 3, and 4;    -   each R^(1A) is independently selected from the group consisting        of: —H —C₁₋₈alkyl, —C₁₋₈haloalkyl, —(CH₂)_(n)CONH₂,        —(CH₂)_(n)COOH, —(CH₂)_(n)aryl, —(CH₂)_(n)heteroaryl,        —(CH₂)_(n)cycloalkyl, and —(CH₂)_(n)heterocycloalkyl, said        —(CH₂)_(n)aryl, —(CH₂)_(n)heteroaryl, —(CH₂)_(n)cycloalkyl, and        —(CH₂)_(n)heterocycloalkyl each optionally substituted with one        or more members, each independently selected from the group        consisting of: -halo, -hydroxy, —C₁₋₄ alkyl, —C₁₋₄ alkoxy, and        -amino, wherein n is independently an integer selected from 0,        1, 2, 3, and 4;    -   each R^(1B) is independently selected from the group consisting        of: —H —C₁₋₈alkyl, —C₁₋₈halo alkyl, —(CH₂)_(n)CONH₂,        —(CH₂)_(n)COOH, —(CH₂)_(n)aryl, —(CH₂)_(n)hetero aryl,        —(CH₂)_(n)cycloalkyl, and —(CH₂)_(n)heterocycloalkyl, wherein n        is independently an integer selected from 0, 1, 2, 3, and 4;    -   each R^(1C) is independently selected from the group consisting        of: —H —C₁₋₈alkyl, —C₁₋₈halo alkyl, —(CH₂)_(n)CONH₂,        —(CH₂)_(n)COOH, —(CH₂)_(n)aryl, —(CH₂)_(n)hetero aryl,        —(CH₂)_(n)cycloalkyl, and —(CH₂)_(n)heterocycloalkyl, wherein n        is independently an integer selected from 0, 1, 2, 3, and 4;    -   R⁹ and R¹⁰ are each independently selected from the group        consisting of: —H, —C₁₋₈alkyl, and —C₁₋₈haloalkyl, said alkyl        optionally substituted with up to 3 members, each independently        selected from the group consisting of: -amino, -hydroxy and        -carboxyl; or optionally R⁹ and R¹⁰ taken together with the        carbon to which they are attached can form an optionally        substituted five membered heteroaryl or heterocycloalkyl ring;        and    -   R¹¹ and R¹² are each independently selected from the group        consisting of: —H, —C₁₋₆alkyl, and —C₁₋₆haloalkyl, said        —C₁₋₆alkyl, and —C₁₋₆haloalkyl optionally substituted with up to        3 members, each independently selected from the group consisting        of: -hydroxy and amino.

In some embodiments, a chemical entity corresponds to the (1R,5R)enantiomer of Formula (I):

In some embodiments, a chemical entity corresponds to the (1S,5S)enantiomer of Formula (I):

In some embodiments, R¹ is —H; or

-   -   R¹ is —C₁₋₆alkyl, optionally substituted with one or more        members, each independently selected from the group consisting        of: -halo, -hydroxy, -alkoxy, -amino and -carboxyl; or    -   R¹ is —C₃₋₈alkenyl or —C₃₋₈alkynyl, each optionally substituted        with one or more members, each independently selected from the        group consisting of: -halo, -hydroxy, —C₁₋₄alkyl, —C₁₋₄alkoxy,        and amino; or    -   R¹ is —(CH₂)_(n)aryl, —(CH₂)_(n)heteroaryl,        —(CH₂)_(n)cycloalkyl, or —(CH₂)_(n)heterocycloalkyl, each        optionally substituted with one or more members, each        independently selected from the group consisting of: -halo,        -hydroxy, —C₁₋₄alkyl, —C₁₋₄alkoxy, and -amino, wherein n is        independently an integer selected from 0, 1, 2, 3, and 4; or    -   R¹ is —CR⁵R⁶NR⁷R⁸, —CHR⁹R¹⁰, or —C(OH)R¹¹R¹² wherein R⁷ and R⁸        are independently selected from the group consisting of: —H,        —C₁₋₈alkyl, and —C₁₋₈haloalkyl;    -   R⁵ and R⁶ are each independently selected from the group        consisting of: —H, -halo, —NH₂, —C₁₋₈alkyl, —C₁₋₈haloalkyl,        —(CH₂)_(n)CONH₂, —(CH₂)_(n)COOH, —(CH₂)_(n)aryl,        —(CH₂)_(n)heteroaryl, —(CH₂)_(n)cycloalkyl, and        —(CH₂)_(n)heterocycloalkyl, each optionally substituted with one        or more members, each independently selected from the group        consisting of: -guanidyl, -urea, -halo, -alkyl, -hydroxy,        -amino, -alkoxy, -2,3-dihydro-1H-pyrrole-1-carboxamide, wherein        n is independently an integer selected from 0, 1, 2, 3, and 4;    -   R⁹ and R¹⁰ are each independently selected from the group        consisting of: —H, —C₁₋₈alkyl, and —C₁₋₈haloalkyl, said alkyl        optionally substituted with up to 3 members, each independently        selected from the group consisting of -amino, -hydroxy, and        -carboxyl; or optionally R⁹ and R¹⁰ taken together with the        carbon to which they are attached can form an optionally        substituted five membered heteroaryl or heterocycloalkyl ring;        and    -   R¹¹ and R¹² are independently selected from the group consisting        of: —H, —C₁₋₆alkyl, and —C₁₋₆haloalkyl, said —C₁₋₆alkyl, and        —C₁₋₆haloalkyl optionally substituted with up to 3 members, each        independently selected from the group consisting of: -hydroxy        and -amino.

In some embodiments, R¹ is —H; or

-   -   —C₁₋₆alkyl, optionally substituted with one or more members,        each independently selected from the group consisting of: -halo,        -hydroxy, -alkoxy, -amino and -carboxyl; or    -   —C₃₋₈alkenyl or —C₃₋₈alkynyl, each optionally substituted with        one or more members, each independently selected from the group        consisting of: -halo, -hydroxy, —C₁₋₄alkyl, —C₁₋₄alkoxy, and        amino; or    -   —(CH₂)_(n)aryl, —(CH₂)_(n)heteroaryl, —(CH₂)_(n)cycloalkyl, or        —(CH₂)_(n)heterocycloalkyl, each optionally substituted with one        or more members, each independently selected from the group        consisting of: -halo, -hydroxy, —C₁₋₄alkyl, —C₁₋₄alkoxy, and        -amino, wherein n is independently an integer selected from 0,        1, 2, 3, and 4; or    -   —COR², —CONR³R⁴, —CR⁵R⁶NR⁷R⁸, —CHR⁹R¹⁰, and —C(OH)R¹¹R¹²,    -   wherein R², R³, R⁴, R⁷ and R⁸ are independently selected from        the group consisting of: —H, —C₁₋₈alkyl, and —C₁₋₈haloalkyl;    -   R⁵ and R⁶ are independently selected from the group consisting        of: —H, -halo, —NH₂, —C₁₋₈alkyl, —C₁₋₈haloalkyl,        —(CH₂)_(n)CONH₂, —(CH₂)_(n)COOH, —(CH₂)_(n)aryl,        —(CH₂)_(n)heteroaryl, —(CH₂)_(n)cycloalkyl, and        —(CH₂)_(n)heterocycloalkyl, each optionally substituted with one        or more members, each independently selected from the group        consisting of: -guanidyl, -urea, -halo, -alkyl, -hydroxy,        -amino, -alkoxy, -2,3-dihydro-1H-pyrrole-1-carboxamide, wherein        n is independently an integer selected from 0, 1, 2, 3, and 4;    -   R⁹ and R¹⁰ are independently selected from the group consisting        of: —H, —C₁₋₈alkyl, and —C₁₋₈haloalkyl, said alkyl optionally        substituted with up to 3 members, each independently selected        from the group consisting of: -amino, -hydroxy and -carboxyl; or        optionally R⁹ and R¹⁰ taken together with the carbon to which        they are attached can form a five membered heteroaryl or        heterocycloalkyl ring; and    -   R¹¹ and R¹² are independently selected from the group consisting        of: —H, —C₁₋₆alkyl, and —C₁₋₆haloalkyl, optionally substituted        with up to 3 members, each independently selected from the group        consisting of: -hydroxy and amino.

In some embodiments, R¹ is —CR⁵R⁶NR⁷R⁸ or —CR⁹R¹⁰,

-   -   wherein R⁵ and R⁶ are independently selected from the group        consisting of: —H, —F, —Cl, —Br, —NH₂, -methyl, -ethyl,        -n-propyl, -isopropyl, -butyl, -pentyl, —NH₂, —C₁₋₈haloalkyl,        —(CH₂)_(n)CONH₂, —(CH₂)_(n)COOH, —(CH₂)_(n)aryl,        —(CH₂)_(n)benzyl, —(CH₂)_(n)heteroaryl, —(CH₂)indole,        —(CH₂)imidazole, —(CH₂)_(n)cycloalkyl,        —(CH₂)_(n)heterocycloalkyl, —(CH₂), pyrrolidine, —(CH₂)furan,        and —(CH₂)_(n)thiophene, optionally substituted with up to 3        members, each independently selected from the group consisting        of: -guanidyl, -urea, -halo, -alkyl, -hydroxy, -amino, -alkoxy,        -2,3-dihydro-1H-pyrrole-1-carboxamide, —(CH²)_(n)NR^(1A)R^(1B),        —(CH₂)_(n)OR^(1C), —(CH₂)_(n)SR^(1C) and —(CH₂)_(n)SeR^(1C),        wherein n is independently an integer selected from 0, 1, 2, 3,        and 4;    -   each R^(1A) is independently selected from the group consisting        of: —H —C₁₋₈alkyl, —C₁₋₈halo alkyl, —(CH₂)_(n)aryl,        —(CH₂)_(n)hetero aryl, —(CH₂)_(n)cyclo alkyl, and        —(CH₂)_(n)heterocycloalkyl, wherein n is independently an        integer selected from 0, 1, 2, 3, and 4;    -   each R^(1C) is independently selected from the group consisting        of: —H —C₁₋₈alkyl, —C₁₋₈halo alkyl, —(CH₂)_(n)aryl,        —(CH₂)_(n)hetero aryl, —(CH₂)_(n)cyclo alkyl, and        —(CH₂)_(n)heterocycloalkyl, wherein n is independently an        integer selected from 0, 1, 2, 3, and 4;    -   each R^(1C) is independently selected from the group consisting        of: —H —C₁₋₈alkyl, —C₁₋₈haloalkyl, —(CH₂)_(n)aryl,        —(CH₂)_(n)heteroaryl, —(CH₂)_(n)cycloalkyl, and        —(CH₂)_(n)heterocycloalkyl, wherein n is independently an        integer selected from 0, 1, 2, 3, and 4;    -   R⁷ and R⁸ are H; and R⁹ and R¹⁰ are independently selected from        the group consisting of: —H, —C₁₋₈alkyl, and —C₁₋₈haloalkyl; or        optionally R⁹ and R¹⁰ taken together with the carbon to which        they are attached can form an optionally substituted five        membered heteroaryl or heterocycloalkyl ring.

In some embodiments, R¹ includes —H.

In some embodiments, R¹ includes —C₁₋₆alkyl, optionally substituted withone or more members, each independently selected from the groupconsisting of: -halo, -hydroxy, -alkoxy, -amino and -carboxyl.

In some embodiments, R¹ includes —C₃₋₈alkenyl, optionally substitutedwith one or more members, each independently selected from the groupconsisting of: -halo, -hydroxy, —C₁₋₄alkyl, —C₁₋₄alkoxy, and -amino.

In some embodiments, R¹ includes —C₃₋₈alkynyl, each optionallysubstituted with one or more members, each independently selected fromthe group consisting of: -halo, -hydroxy, —C₁₋₄alkyl, —C₁₋₄alkoxy, and-amino.

In some embodiments, R¹ includes —(CH₂)_(n)aryl, optionally substitutedwith one or more members, each independently selected from the groupconsisting of: -halo, -hydroxy, —C₁₋₄alkyl, —C₁₋₄alkoxy, and -amino,wherein n is independently an integer selected from 0, 1, 2, 3, and 4;

In some embodiments, R¹ includes —(CH₂)_(n)heteroaryl, optionallysubstituted with one or more members, each independently selected fromthe group consisting of: -halo, -hydroxy, —C₁₋₄alkyl, —C₁₋₄alkoxy, and-amino; wherein n is independently an integer selected from 0, 1, 2, 3,and 4;

-   -   In some embodiments, R¹ includes —(CH₂)_(n)cycloalkyl,        optionally substituted with one or more members, each        independently selected from the group consisting of: -halo,        -hydroxy, —C₁₋₄alkyl, —C₁₋₄alkoxy, and -amino; wherein n is        independently an integer selected from 0, 1, 2, 3, and 4;    -   In some embodiments, R¹ includes —(CH₂)_(n)heterocycloalkyl,        optionally substituted with one or more members, each        independently selected from the group consisting of: -halo,        -hydroxy, —C₁₋₄alkyl, —C₁₋₄alkoxy, and -amino; wherein n is        independently an integer selected from 0, 1, 2, 3, and 4.

In some embodiments, R¹ includes —COR², wherein R² is selected from thegroup consisting of: —H, —C₁₋₈alkyl, and —C₁₋₈haloalkyl.

In some embodiments, R¹ includes —CONR³R⁴, wherein R³ and R⁴ areindependently selected from the group consisting of: —H, —C₁₋₈alkyl, and—C₁₋₈haloalkyl.

In some embodiments, R¹ includes —CR⁵R⁶NR⁷R⁸, wherein R⁷ and R⁸ areindependently selected from the group consisting of: —H, —C₁₋₈alkyl, and—C₁₋₈haloalkyl; and R⁵ and R⁶ are independently selected from the groupconsisting of: —H, -halo, —NH₂, —C₁₋₈alkyl, —C₁₋₈haloalkyl,—(CH₂)_(n)CONH₂, —(CH₂)_(n)COOH, —(CH₂)_(n)aryl, —(CH₂)_(n)heteroaryl,—(CH₂)_(n)cycloalkyl, and —(CH₂)_(n)heterocycloalkyl, each optionallysubstituted with one or more members, each independently selected fromthe group consisting of: -guanidyl, -urea, -halo, -alkyl, -hydroxy,-amino, -alkoxy, -2,3-dihydro-1H-pyrrole-1-carboxamide, wherein n isindependently an integer, selected from 0, 1, 2, 3, and 4.

In some embodiments, R¹ includes —CR⁵R⁶NR⁷R⁸, wherein R⁷ and R⁸ areindependently selected from the group consisting of: —H, —C₁₋₈alkyl, and—C₁₋₈haloalkyl; and R⁵ and R⁶ are each independently selected from thegroup consisting of: —H, -halo, —NH₂, —C₁₋₈alkyl, —C₁₋₈haloalkyl,—(CH₂)_(n)CONH₂, —(CH₂)_(n)COOH, —(CH₂)_(n)aryl, —(CH₂)_(n)heteroaryl,—(CH₂)_(n)cycloalkyl, and —(CH₂)_(n)heterocycloalkyl, each optionallysubstituted with one or more members, each independently selected fromthe group consisting of: -guanidyl, -urea, -halo, -alkyl, -hydroxy,-amino, -alkoxy, -2,3-dihydro-1H-pyrrole-1-carboxamide,—(CH₂)_(n)CONR^(1A)R^(1B), —(CH₂)_(n)NHC(═O)R^(1A),—(CH₂)_(n)NR^(1A)R^(1B), —(CH₂)_(n)OR^(1C), —(CH₂)_(n)SR^(1C) and—(CH₂)_(n)SeR^(1C), wherein n is independently an integer selected from0, 1, 2, 3, and 4;

-   -   each R^(1A) is independently selected from the group consisting        of: —H —C₁₋₈alkyl, —C₁₋₈haloalkyl, —(CH₂)_(n)CONH₂,        —(CH₂)_(n)COOH, —(CH₂)_(n)aryl, —(CH₂)_(n)heteroaryl,        —(CH₂)_(n)cycloalkyl, and —(CH₂)_(n)heterocycloalkyl, said        —(CH₂)_(n)aryl, —(CH₂)_(n)heteroaryl, —(CH₂)_(n)cycloalkyl, and        —(CH₂)_(n)heterocycloalkyl each optionally substituted with one        or more members, each independently selected from the group        consisting of: -halo, -hydroxy, —C₁₋₄ alkyl, —C₁₋₄alkoxy, and        -amino, wherein n is independently an integer selected from 0,        1, 2, 3, and 4;    -   each R^(1′) is independently selected from the group consisting        of: —H —C₁₋₈alkyl, —C₁₋₈haloalkyl, —(CH₂)_(n)CONH₂,        —(CH₂)_(n)COOH, —(CH₂)_(n)aryl, —(CH₂)_(n)heteroaryl,        —(CH₂)_(n)cycloalkyl, and —(CH₂)_(n)heterocycloalkyl, wherein n        is independently an integer selected from 0, 1, 2, 3, and 4; and    -   each R^(1C) is independently selected from the group consisting        of: —H —C₁₋₈alkyl, —C₁₋₈haloalkyl, —(CH₂)_(n)CONH₂,        —(CH₂)_(n)COOH, —(CH₂)_(n)aryl, —(CH₂)_(n)heteroaryl,        —(CH₂)_(n)cycloalkyl, and —(CH₂)_(n)heterocycloalkyl, wherein n        is independently an integer selected from 0, 1, 2, 3, and 4.

In some embodiments, R¹ includes —CHR⁹R¹⁰, wherein R⁹ and R¹⁰ areindependently selected from the group consisting of: —H, —C₁₋₈alkyl,—C₁₋₈haloalkyl, said alkyl optionally substituted with up to 3-amino,-hydroxy, and -carboxyl groups; or optionally R⁹ and R¹⁰ taken togetherwith the carbon to which they are attached can form an optionallysubstituted five-membered heteroaryl or heterocycloalkyl ring.

In some embodiments, R¹ includes —C(OH)R¹¹R¹², wherein R¹¹ and R¹² areindependently selected from the group consisting of: —H, —C₁₋₆alkyl and—C₁₋₆haloalkyl, optionally substituted with up to 3 members, eachindependently selected from the group consisting of: -hydroxy and-amino.

In some embodiments, the heteroatom is selected from the groupconsisting of N (nitrogen), O (oxygen), and S (sulfur).

In some embodiments, the heteroatom is selected from the groupconsisting of N (nitrogen), O (oxygen), Se (selenium), and S (sulfur).

In some embodiments, the heteroatom includes N (nitrogen).

In some embodiments, the heteroatom includes O (oxygen).

In some embodiments, the heteroatom includes S (sulfur).

In some embodiments, the heteroatom includes Se (selenium).

In some embodiments, the disclosure provides a chemical entity ofFormula (I), wherein R¹ includes an analog of a naturally occurringamino acid.

In some embodiments, the disclosure provides a chemical entity ofFormula (I), wherein R¹ includes an analog of a known, non-naturallyoccurring amino acid. Such known, non-naturally occurring, amino acidsinclude β-amino acids (β3 and β2), homo-amino acids, proline- andpyruvic acid derivatives, triple-substituted alanine derivatives,glycine derivatives, ring-substituted phenylalanine and tyrosinederivatives, linear core amino acids, and N-methyl amino acids.

In some embodiments, the chemical entity is selected from the groupconsisting of compounds of Formula (I), pharmaceutically acceptablesalts of compounds of Formula (I), pharmaceutically acceptable chelatesof compounds of Formula (I), pharmaceutically acceptable solvates ofcompounds of Formula (I), pharmaceutically acceptable metabolites ofcompounds of Formula (I), and pharmaceutically acceptable prodrugs ofcompounds of Formula (I).

In some embodiments, the chemical entity is selected from the groupconsisting of compounds of Formula (I) and pharmaceutically acceptablesalts of compounds of Formula (I).

In some embodiments, the disclosure provides a compound selected fromthe group consisting of:

-   (1R,5R)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;    (1R,5R)-5-(2-chlorophenyl)-3-methyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-5-(2-chlorophenyl)-3-(1-hydroxyethyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-((S)-1-amino-2-methylpropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-(aminomethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-5-(2-chlorophenyl)-3-fluorocarbonyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-5-(2-chlorophenyl)-3-((S)-1,5-diaminopentyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-((S)-1-aminoethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-5-(2-chlorophenyl)-3-phenyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-((1S,2R)-1-amino-2-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-((S)-1-amino-3-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-((S)-1-amino-2-phenylethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-((S)-1-amino-2-(4-hydroxyphenyl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-((S)-1-amino-2-(1H-indol-3-yl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-((S)-1-amino-2-(1H-imidazol-4-yl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-5-(2-chlorophenyl)-3-(pyrrolidin-2-yl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (S)-3-amino-3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)propanoic    acid;-   (S)-4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)butanoic    acid;-   (S)-4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)butanamide;-   (S)-3-amino-3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)propanamide;-   (1R,5R)-3-((S)-1-amino-3-(methylthio)propyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-((R)-1-amino-2-mercaptoethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-((S)-1-amino-2-hydroxyethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-((S)-1-amino-2-methoxyethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   1-((S)-4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)butyl)guanidine;-   (1R,5R)-5-(2-chlorophenyl)-3-ethyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)-2-hydroxypropanoic    acid;-   2-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)methyl)-2-hydroxysuccinic    acid;-   5-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)pentanoic    acid;-   3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)-2,3-dihydroxypropanoic    acid;-   3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)propanoic    acid;-   (1R,5R)-5-(2-chlorophenyl)-3-heptyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-(1-amino-2-hydroselenoethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-5-(2-chlorophenyl)-3-(2-(methylamino)ethyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-5-(2-chlorophenyl)-3-(1,2-diaminoethyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-(2-amino-1-hydroxyethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-(3-aminopropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-(4-aminobutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-(3-aminopentyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-(1-amino-3-hydroxypropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-5-(2-chlorophenyl)-3-(1,4-diaminobutyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)-N-ethylbutanamide;-   (1R,5R)-5-(2-chlorophenyl)-3-(1,5-diamino-4-hydroxypentyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   1-(4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)butyl)urea;-   1-(5-amino-5-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)pentyl)urea;-   1-(5-amino-5-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)pentyl)guanidine;-   1-(2-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)ethyl)guanidine;-   (1R,5R)-3-(1-amino-2-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-(1-amino-2-(5-hydroxy-1H-indol-3-yl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-(1-amino-2-(5-methyl-1H-indol-3-yl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-(2-(1H-indol-3-yl)-1-(methylamino)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-5-(2-chlorophenyl)-3-(4-hydroxypyrrolidin-2-yl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-(1-amino-2-hydroxy-3-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-5-(2-chlorophenyl)-3-(1-(methylamino)ethyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-(2-aminopropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   N-(5-amino-5-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)pentyl)-3-methyl-3,4-dihydro-2H-pyrrole-2-carboxamide;-   (1R,5R)-3-(1-amino-3-hydroxy-2-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-(1-amino-2,2-dimethylpropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-(amino(3-amino-4-hydroxyphenyl)methyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-(1-amino-2-hydroxy-2-phenylethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;    and-   (1R,5R)-3-(1-amino-2-(4-methoxyphenyl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;    -   or    -   pharmaceutically acceptable salts thereof.

In some embodiments, the disclosure provides a compound selected fromthe group consisting of:

-   (1S,5S)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1S,5S)-5-(2-chlorophenyl)-3-methyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1S,5S)-5-(2-chlorophenyl)-3-(1-hydroxyethyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1S,5S)-3-((S)-1-amino-2-methylpropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1S,5S)-3-(aminomethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1S,5S)-5-(2-chlorophenyl)-3-fluorocarbonyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1S,5S)-5-(2-chlorophenyl)-3-((S)-1,5-diaminopentyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1S,5S)-3-((S)-1-aminoethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1S,5S)-5-(2-chlorophenyl)-3-phenyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1S,5S)-3-((1S,2R)-1-amino-2-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1S,5S)-3-((S)-1-amino-3-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1S,5S)-3-((S)-1-amino-2-phenylethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1S,5S)-3-((S)-1-amino-2-(4-hydroxyphenyl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1S,5S)-3-((S)-1-amino-2-(1H-indol-3-yl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1S,5S)-3-((S)-1-amino-2-(1H-imidazol-4-yl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1S,5S)-5-(2-chlorophenyl)-3-(pyrrolidin-2-yl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (S)-3-amino-3-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)propanoic    acid;-   (S)-4-amino-4-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)butanoic    acid;-   (S)-4-amino-4-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)butanamide;-   (S)-3-amino-3-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)propanamide;-   (1S,5S)-3-((S)-1-amino-3-(methylthio)propyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1S,5S)-3-((R)-1-amino-2-mercaptoethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1S,5S)-3-((S)-1-amino-2-hydroxyethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1S,5S)-3-((S)-1-amino-2-methoxyethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   1-((S)-4-amino-4-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)butyl)guanidine;-   (1S,5S)-5-(2-chlorophenyl)-3-ethyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   3-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)-2-hydroxypropanoic    acid;-   2-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)methyl)-2-hydroxysuccinic    acid;-   5-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)pentanoic    acid;-   3-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)-2,3-dihydroxypropanoic    acid;-   3-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)propanoic    acid;-   (1S,5S)-5-(2-chlorophenyl)-3-heptyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1S,5S)-3-(1-amino-2-hydroselenoethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1S,5S)-5-(2-chlorophenyl)-3-(2-(methylamino)ethyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1S,5S)-5-(2-chlorophenyl)-3-(1,2-diaminoethyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1S,5S)-3-(2-amino-1-hydroxyethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1S,5S)-3-(3-aminoprop    yl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1S,5S)-3-(4-aminobutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1S,5S)-3-(3-aminopentyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1S,5S)-3-(1-amino-3-hydroxyprop    yl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1S,5S)-5-(2-chlorophenyl)-3-(1,4-diaminobutyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   4-amino-4-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)-N-ethylbutanamide;-   (1S,5S)-5-(2-chlorophenyl)-3-(1,5-diamino-4-hydroxypentyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   1-(4-amino-4-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)butyl)urea;-   1-(5-amino-5-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)pentyl)urea;-   1-(5-amino-5-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)pentyl)guanidine;-   1-(2-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)ethyl)guanidine;-   (1S,5S)-3-(1-amino-2-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1S,5S)-3-(1-amino-2-(5-hydroxy-1H-indol-3-yl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1S,5S)-3-(1-amino-2-(5-methyl-1H-indol-3-yl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1S,5S)-3-(2-(1H-indol-3-yl)-1-(methylamino)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1S,5S)-5-(2-chlorophenyl)-3-(4-hydroxypyrrolidin-2-yl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1S,5S)-3-(1-amino-2-hydroxy-3-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1S,5S)-5-(2-chlorophenyl)-3-(1-(methylamino)ethyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1S,5S)-3-(2-aminopropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;    N-(5-amino-5-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)pentyl)-3-methyl-3,4-dihydro-2H-pyrrole-2-carboxamide;-   (1S,5S)-3-(1-amino-3-hydroxy-2-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1S,5S)-3-(1-amino-2,2-dimethylpropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1S,5S)-3-(amino(3-amino-4-hydroxyphenyl)methyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1S,5S)-3-(1-amino-2-hydroxy-2-phenylethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;    and-   (1S,5S)-3-(1-amino-2-(4-methoxyphenyl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;    -   or    -   pharmaceutically acceptable salts thereof.

In some embodiments, the disclosure provides a compound selected fromthe group consisting of:

-   (1R,5R)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-5-(2-chlorophenyl)-3-methyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-5-(2-chlorophenyl)-3-(1-hydroxyethyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-((S)-1-amino-2-methylpropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-(aminomethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-5-(2-chlorophenyl)-3-fluorocarbonyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-5-(2-chlorophenyl)-3-((S)-1,5-diaminopentyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-((S)-1-aminoethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-5-(2-chlorophenyl)-3-phenyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-((1S,2R)-1-amino-2-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-((S)-1-amino-3-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-((S)-1-amino-2-phenylethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-((S)-1-amino-2-(4-hydroxyphenyl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-((S)-1-amino-2-(1H-indol-3-yl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-((S)-1-amino-2-(1H-imidazol-4-yl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-5-(2-chlorophenyl)-3-(pyrrolidin-2-yl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (S)-3-amino-3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)propanoic    acid;-   (S)-4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)butanoic    acid;-   (S)-4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)butanamide;-   (S)-3-amino-3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)propanamide;-   (1R,5R)-3-((S)-1-amino-3-(methylthio)propyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-((R)-1-amino-2-mercaptoethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-((S)-1-amino-2-hydroxyethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-((S)-1-amino-2-methoxyethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;    and-   1-((S)-4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)butyl)guanidine;    -   or    -   pharmaceutically acceptable salts thereof.

In some embodiments, the disclosure provides a compound selected fromthe group consisting of:

-   (1R,5R)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-5-(2-chlorophenyl)-3-methyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-5-(2-chlorophenyl)-3-(1-hydroxyethyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-((S)-1-amino-2-methylprop    yl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-(aminomethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-5-(2-chlorophenyl)-3-fluorocarbonyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-5-(2-chlorophenyl)-3-((S)-1,5-diaminopentyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;    and-   (1R,5R)-3-((S)-1-aminoethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;    -   or    -   pharmaceutically acceptable salts thereof.

In some embodiments, the disclosure provides a compound selected fromthe group consisting of:

-   (1R,5R)-3-(1-amino-2-hydro s    elenoethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-5-(2-chlorophenyl)-3-(2-(methylamino)ethyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-5-(2-chlorophenyl)-3-(1,2-diaminoethyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;    (1R,5R)-3-(2-amino-1-hydroxyethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-(3-aminoprop    yl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-(4-aminobutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-(3-aminopentyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-(1-amino-3-hydroxyprop    yl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-5-(2-chlorophenyl)-3-(1,4-diaminobutyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)-N-ethylbutanamide;-   (1R,5R)-5-(2-chlorophenyl)-3-(1,5-diamino-4-hydroxypentyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   1-(4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)butyl)urea;-   1-(5-amino-5-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)pentyl)urea;-   1-(5-amino-5-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)pentyl)guanidine;-   1-(2-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)ethyl)guanidine;-   (1R,5R)-3-(1-amino-2-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-(1-amino-2-(5-hydroxy-1H-indol-3-yl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-(1-amino-2-(5-methyl-1H-indol-3-yl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-(2-(1H-indol-3-yl)-1-(methylamino)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-5-(2-chlorophenyl)-3-(4-hydroxypyrrolidin-2-yl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-(1-amino-2-hydroxy-3-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-5-(2-chlorophenyl)-3-(1-(methylamino)ethyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-(2-aminopropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   N-(5-amino-5-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)pentyl)-3-methyl-3,4-dihydro-2H-pyrrole-2-carboxamide;-   (1R,5R)-3-(1-amino-3-hydroxy-2-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-(1-amino-2,2-dimethylpropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-(amino(3-amino-4-hydroxyphenyl)methyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   (1R,5R)-3-(1-amino-2-hydroxy-2-phenylethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;    and-   (1R,5R)-3-(1-amino-2-(4-methoxyphenyl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;    -   or    -   pharmaceutically acceptable salts thereof.

In some embodiments, the disclosure provides a compound selected fromthe group consisting of:

-   (1R,5R)-5-(2-chlorophenyl)-3-ethyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;-   3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)-2-hydroxypropanoic    acid;-   2-(((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)methyl)-2-hydroxysuccinic    acid;-   5-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)pentanoic    acid;-   3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)-2,3-dihydroxypropanoic    acid;-   3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)propanoic    acid; and-   (1R,5R)-5-(2-chlorophenyl)-3-heptyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;    -   or    -   pharmaceutically acceptable salts thereof.

In some embodiments, a chemical entity of the present disclosureincludes an amino acid conjugate. Preferably, the amino acids of thepresent technology are Generally Regarded As Safe (GRAS) or non-toxic atthe concentrations released into the systemic circulation.

Amino acids suitable for use in compounds and compositions can bebroadly classified into standard amino acids, non-standard amino acids,and synthetic amino acids.

Standard amino acids, or proteinogenic amino acids, include but are notlimited to the currently known amino acids that make up the monomericunits of proteins that are encoded in the universal genetic code oforganisms. Standard amino acids include alanine, arginine, asparagine,aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine,isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine,threonine, tryptophan, tyrosine and valine.

Non-standard amino acids are not encoded by the standard genetic codeand include chemical modifications of standard amino acids alreadyincorporated in the proteins, as well as amino acids not found inproteins but still present in living organisms. Examples of non-standardamino acids include ornithine, homoarginine, citrulline, homocitrulline,homoserine, theanine, γ-aminobutyric acid, sarcosine, cartinine,2-aminoadipic acid, pantothenic acid, taurine, hypotaurine, lanthionine,thiocysteine, cystathionine, homocysteine, β-amino acids such asβ-alanine, β-aminoisobutyric acid, β-leucine, β-lysine, β-arginine,β-tyrosine, β-phenylalanine, isoserine, β-glutamic acid, β-tyrosine,β-dopa (3,4-dihydroxy-L-phenylalanine), α,α-disubstituted amino acidssuch as 2-aminoisobutyric acid, isovaline, di-n-ethylglycine, N-methylacids such as N-methyl-alanine, L-abrine, hydroxy-amino acids such as4-hydroxyproline, 5-hydroxylysine, 3-hydroxyleucine,4-hydroxyisoleucine, 5-hydroxy-L-tryptophan, cyclic amino acids such as1-aminocyclopropyl-1-carboxylic acid, azetidine-2-carboxylic acid andpipecolic acid. Non-standard amino acids also include selenocysteine andpyrrolysine, which are incorporated into proteins by unique syntheticmechanisms.

Synthetic amino acids do not occur in nature and must be synthesized.

Examples of synthetic amino acids include allylglycine,cyclohexylglycine, N-(4-hydroxyphenyl)glycine, N-(chloroacetyl)glyclineester, 2-(trifluoromethyl)-phenylalanine,4-(hydroxymethyl)-phenylalanine, 4-amino-phenylalanine,2-chlorophenylglycine, 3-guanidino propionic acid, 3,4-dehydro-proline,2,3-diaminobenzoic acid, 2-amino-3-chlorobenzoic acid,2-amino-5-fluorobenzoic acid, allo-isoleucine, tert-leucine,3-phenylserine, isoserine, 3-aminopentanoic acid, 2-amino-octanedioicacid, 4-chloro-β-phenylalanine, β-homoproline, β-homoalanine,3-amino-3-(3-methoxyphenyl)propionic acid, N-isobutyryl-cysteine,3-amino-tyrosine, 5-methyl-tryptophan, 2,3-diaminopropionic acid,5-aminovaleric acid, and 4-(dimethylamino)cinnamic acid.

In some embodiments, a chemical entity of the present disclosureincludes a carboxylic acid conjugate. Preferably, the carboxylic acidsof the present disclosure are Generally Regarded As Safe (GRAS) ornon-toxic at the concentrations released into the systemic circulation.

In some embodiments, Formula (I) compounds are hydrolyzed chemically,enzymatically or by a combination of chemical and enzymatic processes,and release HNK upon administration to a subject. In some embodiments,Formula (I) compounds may be pharmacologically inactive or havepharmacological activity that is limited or different from HNK, andconsequently, in certain embodiments, may follow a metabolic pathwaythat differs from HNK.

In some embodiments, the chemical entity is a salt, solvate, conformer,polymorph, or a prodrug of a compound of Formula (I).

Salts

In some embodiments, the disclosure provides pharmaceutically acceptablesalts of the compounds represented by Formula (I), and the use of suchsalts in methods of the present invention.

Examples of pharmaceutically acceptable salts include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,monohydrogen-phosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates, borate, nitrate,propionates, decanoates, caprylates, acrylates, formates, isobutyrates,caproates, heptanoates, propiolates, oxalates, malonates, succinates,suberates, sebacates, fumarates, maleates, butyne-1,4-dioates,hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates,sulfonates, xylenesulfonates, phenylacetates, phenylpropionates,phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates,tartrates, methane-sulfonates, propanesulfonates,naphthalene-1-sulfonates, naphthalene-2-sulfonates, besylate, mesylateand mandelates.

When the compound of Formula (I) contains a basic nitrogen, the desiredpharmaceutically acceptable salt may be prepared by any suitable methodavailable in the art, for example, treatment of the free base with aninorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuricacid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and thelike, or with an organic acid, such as acetic acid, phenylacetic acid,propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid,hydroxymaleic acid, isethionic acid, succinic acid, valeric acid,fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid,salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidylacid, such as glucuronic acid or galacturonic acid, an alpha-hydroxyacid, such as mandelic acid, citric acid, or tartaric acid, an aminoacid, such as aspartic acid, glutaric acid or glutamic acid, an aromaticacid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, orcinnamic acid, a sulfonic acid, such as laurylsulfonic acid,p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, anycompatible mixture of acids such as those given as examples herein, andany other acid and mixture thereof that are regarded as equivalents oracceptable substitutes in light of the ordinary level of skill in thistechnology.

When the compound of Formula (I) is an acid, such as a carboxylic acidor sulfonic acid, the desired pharmaceutically acceptable salt may beprepared by any suitable method, for example, treatment of the free acidwith an inorganic or organic base, such as an amine (primary, secondaryor tertiary), an alkali metal hydroxide, alkaline earth metal hydroxide,any compatible mixture of bases such as those given as examples herein,and any other base and mixture thereof that are regarded as equivalentsor acceptable substitutes in light of the ordinary level of skill inthis technology. Illustrative examples of suitable salts include organicsalts derived from amino acids, such as N-methyl-O-glucamine, lysine,choline, glycine and arginine, ammonia, carbonates, bicarbonates,primary, secondary, and tertiary amines, and cyclic amines, such astromethamine, benzylamines, pyrrolidines, piperidine, morpholine, andpiperazine, and inorganic salts derived from sodium, calcium, potassium,magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

Solvates

In some embodiments, the disclosure provides a solvate of a compound ofFormula (I), or a solvate of a pharmaceutically acceptable salt of acompound of Formula (I), and the use of such solvates in methods ofpresent invention.

Solvates can be formed from the interaction or complexes of compounds ofthe invention with one or more solvents, either in solution or as asolid or crystalline form. Such solvent molecules are those commonlyused in the pharmaceutical art, which are known to be innocuous to therecipient, e.g., water, ethanol, ethylene glycol, and the like. Othersolvents may be used as intermediate solvates in the preparation of moredesirable solvates, such as methanol, methyl t-butyl ether, ethylacetate, methyl acetate, (S)-propylene glycol, (R)-propylene glycol,1,4-butyne-diol, and the like. Hydrates include compounds formed by anincorporation of one or more water molecules.

Polymorphs

In certain embodiments, compounds of Formula (I) may exist incrystalline form. A polymorph (or crystalline form) is a compositionhaving the same chemical formula, but a different solid state or crystalstructure. In addition, certain crystalline forms of compounds ofFormula (I) or pharmaceutically acceptable salts of compounds of Formula(I) are obtainable as co-crystals.

Prodrugs

The term “prodrug” means a precursor of a designated compound that,following administration to a subject, yields the compound in vivo viaone or more physiochemical or physiological processes, such as chemicalhydrolysis or enzymatic cleavage. In some embodiments, more than oneprocess may be required to yield the compound in vivo. For example, acompound of Formula (I), upon administration in vivo, may undergo bothhydrolysis and enzymatic conversion.

In some embodiments, the chemical entities of Formula (I) are prodrugsdesigned to yield, in vivo, a suitable yield of the ketamine metabolite,HNK. That is, in some embodiments, chemical entities of Formula (I) areprecursors of HNK and therefore can yield biologically available HNKupon administration to a subject.

In some embodiments, prodrugs may be obtained from furtherderivatization of compounds of Formula (I). Prodrugs may be generatedusing techniques known or available in the art (e.g., Bundgard (ed.),1985, Design of prodrugs, Elsevier; Krogsgaard-Larsen et al., (eds.),1991, Design and Application of Prodrugs, Harwood Academic Publishers).Prodrugs may be produced, for instance, by derivatizing free carboxylgroups of structures of Formula (I) as amides or alkyl esters, or byderivatizing free hydroxy groups using groups including hemisuccinates,phosphate esters, dimethylaminoacetates, andphosphoryloxymethyloxycarbonyls, following procedures such as thoseoutlined in Fleisher et al., Adv. Drug Delivery Rev. 1996, 19, 115-130.

Metabolites

The present disclosure also relates to a metabolite of a compound ofFormula (I), as defined herein, and salts thereof. The present inventionfurther relates to the use of such metabolites, and salts thereof, inmethods of present invention, including therapeutic methods.

Metabolites of a compound may be determined using routine techniquesknown or available in the art. For example, isolated metabolites can beenzymatically and synthetically produced (e.g., Bertolini et al., J.Med. Chem. 1997, 40, 2011-2016; Shan et al., J. Pharm. Sci. 1997, 86,765-767; Bagshawe, Drug Dev. Res. 1995, 34, 220-230; and Bodor, Adv DrugRes. 1984, 13, 224-231).

In preferred embodiments, the metabolite corresponds to HNK. Withoutbeing limited by mechanism, compounds of Formula (I) may undergo one ormore physiological processes following administration, resulting in HNKand other byproducts. In some embodiments, the byproduct of suchprocesses may include an amino acid or carboxylic acid.

Compositions

Compounds disclosed herein can be administered as the neat chemical, butare preferably administered as a composition. The term “composition,” asin pharmaceutical composition, is intended to encompass a productcomprising the active ingredient(s) and the inert ingredient(s)(pharmaceutically acceptable excipients) that make up the carrier, aswell as any product which results, directly or indirectly, fromcombination, complexation, or aggregation of any two or more of theingredients, or from dissociation of one or more of the ingredients, orfrom other types of reactions or interactions of one or more of theingredients.

Accordingly, in some embodiments, the disclosure provides apharmaceutical composition comprising a chemical entity of any of theembodiments and examples disclosed herein; and a pharmaceuticallyacceptable carrier. In some embodiments, a pharmaceutical compositioncomprises a compound, or pharmaceutically acceptable salt thereof, ofany of the embodiments and examples disclosed herein; and apharmaceutically acceptable carrier. In specific embodiments, apharmaceutical composition comprises a compound of any one of Examples1-61; and a pharmaceutically acceptable carrier.

The pharmaceutical composition may contain a compound or salt of Formula(I) as the only active agent, but preferably contains at least oneadditional active agent. In certain embodiments the pharmaceuticalcomposition is an oral dosage form that contains from about 0.1 mg toabout 1000 mg, from about 1 mg to about 500 mg, or from about 10 mg toabout 200 mg of a compound of Formula (I) and optionally from about 0.1mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100mg to about 800 mg, or from about 200 mg to about 600 mg of anadditional active agent in a unit dosage form.

In some embodiments, compounds of Formula (I), and pharmaceuticallyacceptable salts thereof, are used, alone or in combination with one ormore additional active ingredients, to formulate pharmaceuticalcompositions.

Formulations and Administration

Procedures for preparing various formulations suitable for administeringare known in the art. Examples of potential formulations andpreparations are contained, for example, in the Handbook ofPharmaceutical Excipients, American Pharmaceutical Association (currentedition); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman andSchwartz, editors) current edition, published by Marcel Dekker, Inc., aswell as Remington's Pharmaceutical Sciences (Osol, ed.), 1980,1553-1593.

Any suitable route of administration may be employed for providing ananimal, especially a human, with an effective dosage of a compound ofthe present invention. For example, oral, rectal, topical, parenteral,ocular, pulmonary, nasal, buccal, and the like may be employed. Dosageforms include tablets, troches, dispersions, suspensions, solutions,capsules, creams, ointments, aerosols, and the like.

Suitable carriers, diluents and excipients are well known to thoseskilled in the art and include materials such as carbohydrates, waxes,water soluble and/or swellable polymers, hydrophilic or hydrophobicmaterials, gelatin, oils, solvents, water, and the like. The particularcarrier, diluent, or excipient used will depend upon the means andpurpose for which the compound of the present invention is beingapplied. Some carriers may be listed in more than one class, for examplevegetable oil may be used as a lubricant in some formulations and adiluent in others. Solvents are generally selected based on solventsrecognized by persons skilled in the art as safe (GRAS) to beadministered to an animal. In general, safe solvents are non-toxicaqueous solvents such as water and other non-toxic solvents that aresoluble or miscible in water. Suitable aqueous solvents include water,ethanol, propylene glycol, polyethylene glycols (e.g., PEG400, PEG300),etc. and mixtures thereof. The formulations may also include one or morebuffers, stabilizing agents, surfactants, wetting agents, lubricatingagents, emulsifiers, suspending agents, preservatives, antioxidants,opaquing agents, glidants, processing aids, colorants, sweeteners,perfuming agents, flavoring agents and other known additives to providean elegant presentation of the drug (i.e., a compound of the presentinvention or pharmaceutical composition thereof) or aid in themanufacturing of the pharmaceutical product (i.e., medicament).

The formulations may be prepared using conventional dissolution andmixing procedures. For example, the bulk drug substance (i.e., acompound of the present invention or stabilized form of the compound(e.g., complex with a cyclodextrin derivative or other knowncomplexation agent)) is dissolved in a suitable solvent in the presenceof one or more of the excipients described above. The compound of thepresent invention is typically formulated into pharmaceutical dosageforms to provide an easily controllable and appropriate dosage of thedrug.

The pharmaceutical composition (or formulation) for application may bepackaged in a variety of ways, depending upon the method used toadminister the drug. Generally, an article for distribution includes acontainer having deposited therein the pharmaceutical formulation in anappropriate form. Suitable containers are well-known to those skilled inthe art and include materials such as bottles (plastic and glass),sachets, ampoules, plastic bags, metal cylinders, and the like. Thecontainer may also include a tamper-proof assemblage to preventindiscreet access to the contents of the package. In addition, thecontainer has deposited thereon a label that describes the contents ofthe container. The label may also include appropriate warnings.

The present compounds may be systemically administered, e.g., orally, incombination with a pharmaceutically acceptable vehicle such as an inertdiluent or a similar edible carrier. They may be enclosed in hard orsoft shell gelatin capsules, may be compressed into tablets, or may beincorporated directly with the food of the patient's diet. For oraltherapeutic administration, the active compound may be combined with oneor more excipients and used in the form of ingestible tablets, buccaltablets, troches, capsules, elixirs, suspensions, syrups, wafers, andthe like. Such compositions and preparations should contain at least0.1% of active compound. The percentage of the compositions andpreparations may, of course, be varied and may conveniently be betweenabout 2 to about 60% of the weight of a given unit dosage form. Theamount of active compound in such therapeutically useful compositions issuch that an effective dosage level will be obtained.

The tablets, troches, pills, capsules, and the like may also contain thefollowing: binders such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, fructose, lactose or aspartame or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring may be added. Whenthe unit dosage form is a capsule, it may contain, in addition tomaterials of the above type, a liquid carrier, such as a vegetable oilor a polyethylene glycol. Various other materials may be present ascoatings or to otherwise modify the physical form of the solid unitdosage form. For instance, tablets, pills, or capsules may be coatedwith gelatin, wax, shellac or sugar and the like. A syrup or elixir maycontain the active compound, sucrose or fructose as a sweetening agent,methyl and propylparabens as preservatives, a dye and flavoring such ascherry or orange flavor. Of course, any material used in preparing anyunit dosage form should be pharmaceutically acceptable and substantiallynon-toxic in the amounts employed. In addition, the active compound maybe incorporated into sustained-release preparations and devices.

Carriers may include excipients and diluents and must be of sufficientlyhigh purity and sufficiently low toxicity to render them suitable foradministration to the patient being treated. The carrier can be inert orit can possess pharmaceutical benefits of its own. The amount of carrieremployed in conjunction with the compound is sufficient to provide apractical quantity of material for administration per unit dose of thecompound.

Useful solid carriers may include finely divided solids such as talc,clay, microcrystalline cellulose, silica, alumina, and the like. Usefulliquid carriers include water, alcohols or glycols orwater-alcohol/glycol blends, in which the present compounds can bedissolved or dispersed at effective levels, optionally with the aid ofnon-toxic surfactants. Adjuvants such as fragrances and additionalantimicrobial agents can be added to optimize the properties for a givenuse. The resultant liquid compositions can be applied from absorbentpads, used to impregnate bandages and other dressings, or sprayed ontothe affected area using pump-type or aerosol sprayers.

Thickeners such as synthetic polymers, fatty acids, fatty acid salts andesters, fatty alcohols, modified celluloses or modified mineralmaterials can also be employed with liquid carriers to form spreadablepastes, gels, ointments, soaps, and the like, for application directlyto the skin of the user.

The pharmaceutical compositions can be formulated for oraladministration. Preferred oral dosage forms are formulated for once aday or twice a day administration. The compositions contain between 0.1and 99% weight of a compound of Formula (I). In some embodiments,compositions contain at least about 5% weight of a compound of Formula(I). In some embodiments, compositions contain from about 25% to about50% weight of a compound of Formula (I), or about 5% to 75% weight of acompound of Formula (I).

Dosages

Useful dosages of the compounds of Formula (I) can be determined bycomparing their in vitro activity and in vivo activity in animal models.Methods for the extrapolation of effective dosages in mice, and otheranimals, to humans are known to the art. Useful dosages of the compoundsof Formula (I) can be determined by comparing their in vitro activity,and in vivo activity in animal models. Methods for the extrapolation ofeffective dosages in mice, and other animals, to humans are known to theart (e.g., U.S. Pat. No. 4,938,949).

Optimal dosages to be administered in the therapeutic methods of thepresent invention may be determined by those skilled in the art and willdepend on multiple factors, including the particular composition in use,the strength of the preparation, the mode and time of administration,and the advancement of the disease or condition. Additional factors mayinclude characteristics on the subject being treated, such as age,weight, gender, and diet.

In general, however, a suitable dose will be in the range from about0.01 to about 100 mg/kg, more specifically from about 0.1 to about 100mg/kg, such as 10 to about 75 mg/kg of body weight per day, 3 to about50 mg per kilogram body weight of the recipient per day, 0.5 to 90mg/kg/day, or 1 to 60 mg/kg/day (or any other value or range of valuestherein). The compound is conveniently administered in a unit dosageform; for example, containing about 1 to 1000 mg, particularly about 10to 750 mg, and more particularly, about 50 to 500 mg of activeingredient per unit dosage form.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of temporally-distinctadministrations used according to the compositions and methods of thepresent invention.

Effective amounts or doses of the active agents of the present inventionmay be ascertained by routine methods such as modeling, dose escalationstudies or clinical trials, and by taking into consideration routinefactors, e.g., the mode or route of administration or drug delivery, thepharmacokinetics of the agent, the severity and course of the disease,disorder, or condition, the subject's previous or ongoing therapy, thesubject's health status and response to drugs, and the judgment of thetreating physician. Such compositions and preparations should contain atleast 0.1% of active compound. The percentage of the compositions andpreparations may, of course, be varied and may conveniently be between 2to about 60% of the weight of a given unit dosage form. The amount ofactive compound in such therapeutically useful composition is such thatan effective dosage level will be obtained. An exemplary dose is in therange from about 0.001 to about 200 mg of active agent per kg ofsubject's body weight per day, preferably about 0.05 to 100 mg/kg/day,or about 1 to 35 mg/kg/day, or about 0.1 to 10 mg/kg/daily in single ordivided dosage units (e.g., BID, TID, QID). For a 70-kg human, anillustrative range for a suitable dosage amount is from 1 to 200 mg/day,or about 5 to 50 mg/day.

In certain embodiments a therapeutically effect amount is an amount thatprovide a plasma Cmax of HNK of about of 0.25 mcg/mL to about 125mcg/mL, or about 1 mcg/mL to about 50 mcg/mL.

Methods and Uses

Uses of Isotopically-Labeled Compounds

In one aspect, the present invention provides a method of usingisotopically labeled compounds the present invention in: (i) metabolicstudies (preferably with ¹⁴C), reaction kinetic studies (with, forexample ²H or ³H); (ii) detection or imaging techniques, including drugor substrate tissue distribution assays; or (iii) in radioactivetreatment of patients.

Isotopically labeled compounds and prodrugs of the invention thereof cangenerally be prepared by carrying out the procedures disclosed in theschemes or in the examples and preparations described below bysubstituting a readily available isotopically labeled reagent for anon-isotopically labeled reagent. An ¹⁸F or ¹¹C labeled compound may beparticularly preferred for PET, and an I¹²³ labeled compound may beparticularly preferred for SPECT studies. Further substitution withheavier isotopes such as deuterium (i.e., ²H) may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life or reduced dosage requirements.

Recent research suggests that low-dose ketamine can act as a novel,rapid-acting antidepressant [Naughton et al. 2014]. In fact, a singlesubanesthetic dose infusion of ketamine has rapid and potentantidepressant effects in treatment-resistant major depression andbipolar depression [Iadarola et al. 2015]. Ketamine as an antidepressantagent is of great interest as an alternative to the delayed onset toefficacy, repeated administration and unwanted side effects of currentpharmacotherapeutics, behavioral therapies and electroconvulsive therapy(ECT).

Therapeutic Methods

Generally

In some embodiments, chemical entities of the present invention areuseful in methods (or in the manufacture of a medicament or compositionfor use in such methods) of treating certain disorders by administeringto a subject in need thereof an effective amount of a chemical entity ofthe present invention. In some embodiments, the chemical entity is acompound of Formula (I), or a pharmaceutically acceptable salt thereof.In some embodiments, the subject is a human.

In some embodiments, a chemical entity of Formula (I) may be the onlyactive agent administered in methods disclosed herein or may beadministered together with an additional active agent.

In some embodiments, chemical entities of the present invention areuseful in methods (or in the manufacture of a medicament or compositionfor use in such methods) of enhancing neuronal plasticity an essentialproperty of the brain that can be augmented in healthy animals andimpaired in numerous CNS disorders. Without being limited by mechanism,such chemical entities may enhance neuronal plasticity by enhancingcyclic adenosine monophosphate (cAMP) response element binding protein(CREB) pathway function in cells, resulting in the modulation oftranscription of genes involved in synaptic plasticity. See, e.g., Tullyet al., Nat. Rev. Drug Discov. 2003, 2, 267-277; Alberini, Physiol. Rev.2009, 89, 121-145. Accordingly, the present invention provides a methodof enhancing neuronal plasticity, comprising administering to a subjectin need thereof an effective amount of a chemical entity of the presentinvention. In some embodiments, the chemical entity is a compound ofFormula (I), or a pharmaceutically acceptable salt thereof. In preferredembodiments, the subject is a human.

In some embodiments, chemical entities of the present invention areuseful in methods (or in the manufacture of a medicament or compositionfor use in such methods) to augment the efficiency of trainingprotocols, which facilitate functional reorganization in targeted“domains” (or “functions”) in the brain. Training protocols can bedirected to rehabilitating or enhancing a cognitive or motor function.The training protocol (cognitive or motor training) induces neuronalactivity in specific brain regions and produces improved performance ofa specific brain (cognitive or motor) function. In such protocols,chemical entities may act as “augmenting agents” to shorten the timethat methods of rehabilitating (or enhancing) a cognitive or motorfunction result in improved performance or a functional gain.

Such augmented training therefore comprises a specific training protocolfor a particular brain function, such as that underlying declarativememory, performance of a fine motor skill, a specific locomotorfunction, language acquisition, executive function, etc., and a generaladministration of an augmenting agent.

Neurological Disorders

In some embodiments, chemical entities of the present invention areuseful in methods (or in the manufacture of a medicament or compositionfor use in such methods) of treating a neurological disorder, comprisingadministering to a subject in need thereof an effective amount of achemical entity or composition of the present disclosure. In someembodiments, the chemical entity is a compound of Formula (I), or apharmaceutically acceptable salt thereof. In preferred embodiments, thesubject is a human.

In some embodiments, the methods are directed to a cognitive deficit(“cognitive impairment”) or motor deficit (“motor impairment”)associated with (or “due to”) the neurological disorder. Accordingly, insome embodiments, the disclosure provides a method for treating acognitive deficit associated with a neurological disorder, comprisingadministering to a subject in need thereof an effective amount of achemical entity of Formula (I).

A neurological disorder (or condition or disease) is any disorder of thebody's nervous system. Neurological disorders can be categorizedaccording to the primary location affected, the primary type ofdysfunction involved, or the primary type of cause. The broadestdivision is between peripheral nervous system (PNS) disorders andcentral nervous system (CNS) disorders (such as mental and psychiatricdisorders). Neurological disorders are well-known in the art, and theyinclude, but are not limited to, the following mental and psychiatricdisorders:

-   -   Neurodevelopmental (or “developmental” disorders), such as        intellectual disability disorders (e.g., Rubinstein-Taybi        syndrome, Down syndrome); communication disorders;        autism-spectrum disorders; attention-deficit/hyperactivity        disorders; specific learning, language, or reading (e.g.,        dyslexia) disorders; motor disorders; fetal alcohol spectrum        disorders (FASD); and other neurodevelopmental disorders;    -   Schizophrenia spectrum and other psychotic disorders, such as        schizophrenia, schizotypal (personality) disorder, delusional        disorder, and schizophreniform disorder, and other schizophrenia        spectrum and psychotic disorders;    -   Bipolar and related disorders, such as Bipolar I and II        disorders, cyclothymic disorders, and other bipolar and related        disorders;    -   Depressive disorders, such as major depressive disorder (MDD),        persistent depressive disorder (dysthymia), and other depressive        disorders;    -   Anxiety disorders, such as specific phobia, social anxiety        disorder, panic disorder, and generalized anxiety disorder        (social phobia);    -   Obsessive-compulsive and related disorders, such as        obsessive-compulsive disorder, body dysmorphic disorder, and        other obsessive-compulsive and related disorders;    -   Dissociative disorders, such as dissociative identity disorder,        dissociative amnesia, and other dissociative disorders;    -   Disruptive, impulse-control, and conduct disorders, such as        conduct disorders, antisocial personality disorders, and other        disruptive, impulse-control, and conduct disorders;    -   Trauma- and stressor-related disorders, such as posttraumatic        stress disorder (PTSD), acute stress disorder (ASD), adjustment        disorders, and other trauma- and stressor-related disorders;    -   Feeding and eating disorders, such as anorexia nervosa, bulimia        nervosa, and binge-eating disorder;    -   Sleep-wake disorders, such as insomnia, narcolepsy, parasomnias,        and other sleep-wake disorders;    -   Sexual disorders, such as arousal disorders, desire disorders,        substance and medication-induced dysfunctions, and other sexual        disorders;    -   Substance-related and addictive disorders, such as those        involving alcohol, drugs, stimulants, opioids, tobacco, and        non-substance-related disorders; and other substance-related and        addictive disorders; and    -   Personality disorders, such as paranoid personality disorders,        antisocial and borderline personality disorders, avoidance        personality disorders, and other personality disorders.

In particular embodiments, the disorder is schizophrenia.

In other embodiments, the neurological disorder is an acquired disorder,in which the primary clinical feature is impaired cognition. In otherwords, it is a disorder in which the primary cognitive deficit has notbeen present since birth or very early life and therefore represents adecline from a previously attained level of functioning. Such disorders,which may be referred to herein as “cognitive disorders” or“neurocognitive disorders” include one or more of the following:

-   -   Delirium, such as substance-intoxication (or withdrawal)        delirium, medication-induced delirium, and other forms of        delirium;    -   Dementias and other cognitive impairments due to        neurodegenerative diseases, such as Alzheimer's disease,        Parkinson's disease, Huntington's disease, Lewy body disease,        Pick's disease, a prion disease (e.g., Creutzfeldt-Jakob        disease), Amyotrophic lateral sclerosis (ALS), multiple        sclerosis, frontotemporal lobar degeneration, and corticobasal        degeneration; dementia due to a vascular disease (“vascular        disease”); and other dementias and neurodegenerative diseases;

In some embodiments, the disclosure provides a method of treating aneurological disorder, comprising administering to a patient in needthereof an effective amount of a pharmaceutical composition, wherein theneurological disorder is selected from the group consisting of adepressive disorder, a pain disorder, a cognitive disorder, and aneurodegenerative disorder, and a sleep disorder.

Age-associated cognitive deficits, including age-associated memoryimpairment (AAMI), also referred to as age-related memory impairment(AMI) (See, e.g., Crook et al., Devel. Neuropsychol. 1986, 2, 261-276);and deficits affecting patients in early stages of cognitive decline, asin Mild Cognitive Impairment (MCI) (See, e.g., Arnáiz and Almkvist, ActaNeurol. Scand. Suppl. 2003, 179, 34-41).

Trauma-dependent losses of cognitive function, such as vascular diseasesdue to stroke (e.g., ischemic or hemorrhagic stroke) or ischemia;microvascular disease arising from diabetes or arthrosclerosis;traumatic brain injury (TBI), such as brain trauma, including subduralhematoma and brain tumor; head trauma (closed and penetrating); headinjury; tumors, such as nervous system cancers, including cerebraltumors affecting the thalamic or temporal lobe; hypoxia, and viralinfection (e.g., encephalitis); excitotoxicity; and seizures.

Cognitive impairments due to chemotherapy, such as post-chemotherapycognitive impairments (PCCI); chemotherapy-induced cognitive dysfunctionor impairments; chemo brain; or chemo fog.

Such acquired disorders are not necessarily limited to cognitiveimpairments. For example, trauma related disorders, such as stroke,traumatic brain injury, head trauma, and head injury, may also includeimpairments in other neurological functions, such as impairments inmotor functions.

Migraine variants, such as chronic migraine, basilar migraine,vertebrobasilar migraine, status migrainosus, and other forms ofmigraine;

-   -   As used herein, the terms “Neurodevelopment disorders,”        “Schizophrenia spectrum and other psychotic disorders,” “Mood        disorders,” “Bipolar and related disorders,” “Depressive        disorders,” “Anxiety disorders,” “Obsessive-compulsive and        related disorders,” “Dissociative disorders,” “Disruptive,        impulse-control, and conduct disorders,” “Trauma- and        stressor-related disorders,” “Feeding and eating disorders,”        “Sleep-wake disorders,” “Sexual disorders,” “Substance-related        and addictive disorders,” Personality disorders,” “Delirium,”        “Neurocognitive disorders,” “Delirium,” “Dementias,” and        “Trauma” includes treatment of those mental disorders as        described in the Diagnostic and Statistical Manual of Mental        Disorders (DSM-5; 5^(th) ed., 2013, American Psychiatric        Association). The skilled artisan will recognize that there are        alternative nomenclatures and classification systems for mental        disorders, and that these systems evolve with medical and        scientific progress. Thus the terms described in this paragraph        are intended to include like disorders that are described in        other diagnostic sources.        Depressive Conditions

In some embodiments, chemical entities of the present invention areuseful in methods (or in the manufacture of a medicament or compositionfor use in such methods) of treating a depressive condition (disorder),comprising administering to a subject in need thereof an effectiveamount of a chemical entity or composition of the present disclosure. Inone aspect, the chemical entity is a compound of Formula (I), or apharmaceutically acceptable salt thereof. For example,anti-depressant-like effects of low ketamine doses are associated withelevated AMPA receptor function, supporting favorable physiochemicalproperties for HNK in disclosed methods. See, e.g., Tizabi et al.,Neuroscience 2012, 213, 72-80.

In a specific aspect, the depressive disorder is major depressivedisorder (MDD) (also referred to as “major depression” or “clinicaldepression”). In another aspect, the depressive disorder is persistentdepressive disorder (dysthymia). MDD and dysthymia are among the mostcommon depressive disorders. Other depressive disorders that can betreated include, but are not limited to, psychotic depression,postpartum depression, seasonal affective disorder (SAD), a mooddisorder; depression due to another medical condition such as cancer,chronic pain, chronic stress, post-traumatic stress disorder, or abipolar disorder.

A depressive condition is characterized by one or more depressivesymptoms. “Depressive symptoms” may include feelings of persistentanxiousness, sadness, helplessness, hopelessness, worthlessness, orpessimism; low energy; low mood; restlessness; irritability; fatigue;loss of interest in pleasurable activities or hobbies; aversion toactivity; poor concentration or indecisiveness; excessive guilt;insomnia; excessive sleepiness; overeating; loss of appetite; thoughtsof suicide; and suicide attempts.

The presence, severity, frequency, and duration of depressive symptomsvary on a case to case basis. In some embodiments, a patient may have atleast one, at least two, at least three, at least four, or at least fiveof these symptoms. Depressive symptoms may occur in the context ofdepressive disorders, bipolar disorders, mood disorders due to a generalmedical condition, substance-induced mood disorders, and otherunspecified mood disorders. In addition, depressive symptoms may also bepresent in association with other psychiatric disorders, including, butnot limited to, psychotic disorders, cognitive disorders, eatingdisorders, anxiety disorders and personality disorders. The longitudinalcourse of the disorder, the history, and type of symptoms, and etiologicfactors help distinguish the various forms of mood disorders from eachother.

A “depression symptoms rating scale” refers to any one of a number ofstandardized questionnaires, clinical instruments, or symptominventories utilized to measure symptoms and symptom severity indepression. Such rating scales are often used in clinical studies todefine treatment outcomes, based on changes from the study's entrypoint(s) to endpoint(s). Such depression symptoms rating scales include,but are not limited to, The Quick Inventory of Depressive-SymptomatologySelf-Report (QIDS-SR16), the 17-Item Hamilton Rating Scale of Depression(HRSD17), the 30-Item Inventory of Depressive Symptomatology (IDS-C30),or The Montgomery-Asperg Depression Rating Scale (MADRS). Such ratingsscales may involve patient self-report or be clinician rated. A 50% orgreater reduction in a depression ratings scale score over the course ofa clinical trial (starting point to endpoint) is typically considered afavorable response for most depression symptoms rating scales.“Remission” in clinical studies of depression often refers to achievingat, or below, a particular numerical rating score on a depressionsymptoms rating scale (for instance, less than or equal to 7 on theHRSD17; or less than or equal to 5 on the QIDS-SR16; or less than orequal to 10 on the MADRS). Such a score generally corresponds to minimalsymptoms and therefore a clinically desired outcome.

Accordingly, in some embodiments, the disclosure provides a method fortreating a symptom of depression, comprising administering to a subjectin need thereof a therapeutically effective amount of a chemical entityof Formula (I). In one aspect, the chemical entity is a compound ofFormula (I), or a pharmaceutically acceptable salt thereof. In preferredembodiments, the subject is a human. In one aspect, a therapeuticallyeffective amount is an amount effective to achieve remission on adepression symptoms rating scale. In one aspect, the rating scale isHRSD17, QIDS-R16, or MADRS. In another aspect, a therapeuticallyeffective amount is an amount effective to decrease symptoms, wherein adecrease in depressive symptoms is at least a 50% reduction of symptomsidentified on a depression symptom rating scale, or a score less than orequal to 7 on the HRSD17, or less than or equal to 5 on the QID-SR16, orless than or equal to 10 on the MADRS.

In some embodiments, the methods of the present disclosure can be usedto treat major depressive disorder. Major depressive disorder istypically defined as the presence of one or more major depressiveepisodes that are not better accounted for by psychotic disorder orbipolar disorder. For major depressive disorder, an essential feature isa period of at least 2 weeks during which there is either depressed moodor the loss of interest or pleasure is nearly all activities, and forpersistent depressive disorder, an essential feature is a depressed moodthat occurs for most of the day, for more days that not, for at least 2years, or at least 1 year for children and adolescents. See, AmericanPsychiatry Association Diagnostic and Statistical Manual of MentalDisorders (5th edition).

In connection with treatment, “recovery” means that remission, asdefined herein, has sufficiently been sustained, e.g., for 4 months ormore, without a “relapse” (such that continued well-being is expected).A relapse means that the patient has experienced a return of the sameindex major depressive episode (e.g., severe major depression) beforereaching achieving the criteria for recovery. A “recurrence” refers tothe development of a new major depressive disorder following recovery.

Accordingly, in some embodiments, chemical entities of the presentinvention are useful in methods (or in the manufacture of a medicamentor composition for use in such methods) of treating major depressivedisorder, comprising administering to a subject in need thereof atherapeutically effective amount of a chemical entity or composition ofthe present disclosure. In one aspect, the chemical entity is a compoundof Formula (I), or a pharmaceutically acceptable salt thereof. In someembodiments, treatment results in recovery without a relapse. In someembodiments, treatment prevents relapse in subjects who previouslyachieved symptom remission. In some embodiments, treatment preventsrecurrence in subjects who previously attained recovery from an initialmajor depressive disorder. In some embodiments, treatment preventsrecurrence for a period of 6 months, 1 year, 2 years, or longer.

In some embodiments, the methods of the present disclosure can be usedto treat treatment resistant (or “treatment refractory”) depression. Atreatment resistant patient may be identified as one who fails toexperience alleviation of one or more symptoms of depression (e.g.,persistent anxious or sad feelings, feelings of helplessness,hopelessness, pessimism) despite undergoing one or more standardpharmacological or non-pharmacological treatment. In certainembodiments, a treatment-resistant patient is one who fails toexperience alleviation of one or more symptoms of depression despiteundergoing treatment with two different antidepressant drugs. In otherembodiments, a treatment-resistant patient is one who fails toexperience alleviation of one or more symptoms of depression despiteundergoing treatment with four different antidepressant drugs. Atreatment-resistant patient may also be identified as one who isunwilling or unable to tolerate the side effects of one or more standardpharmacological or non-pharmacological treatment.

Accordingly, in certain embodiments, the invention relates to methodsfor treating treatment-resistant depression by administering to asubject in need thereof an effective amount of a compound of Formula (I)or composition of the present disclosure. In some embodiments, thetreatment-resistant depression is unipolar depression, including majordepression, including unipolar major depression. In some embodiments,the treatment-resistant depression is bipolar depression, including amajor depressive episode associated with a bipolar disorder. In someembodiments, methods of treating depression are contemplated when apatient has suffered depression for e.g., 5, 6, 7, 8 or more weeks, orfor a month or more. In a specific aspect, the chemical entity is acompound of Formula (I), or a pharmaceutically acceptable salt thereof.

In some embodiments, the disclosure provides methods of treatingsuicidal ideation. Suicidal ideations is generally associated withdepressive and other mood disorder. In addition, it also can beassociated with other mental disorders, life events, and family events,all of which may increase the risk of suicidal ideation. For example,many individuals with borderline personality disorder exhibit recurrentsuicidal behavior and suicidal thoughts. Ketamine (and its metabolites)can offer a therapeutic option in patients at imminent risk of suicide.See, e.g., Ballard et al., J. Psych. Res. 2014, 58, 161-166; Wilkinsonand Sanacora, Depress. Anxiety 2016, 33, 711-717.

Accordingly, in specific embodiments, the disclosure provides a methodof treating suicidal ideation, comprising administering to a subject inneed thereof an effective amount of a chemical entity of Formula (I) orcomposition of the present disclosure. In a specific aspect, thechemical entity is a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof. In a specific aspect, suicidal ideation isassociated with a depressive disorder.

In some embodiments, the present disclosure provides methods for rapidlytreating a depressive disorder or condition. Current antidepressantsgenerally take several weeks or more to produce a response. Recentresearch, however, suggests that a single low-dose of ketamine can actas a novel, rapid-acting antidepressant with minimal side effects.Naughton et al., J. Affect. Dis 2014, 156, 24-35; Muller et al., Ther.Adv. Psychopharmacol. 2016, 6, 185-192. Moreover, recent work indicatesthat the metabolism of (R,S)-ketamine to HNK is essential for itsantidepressant effects, and that the (2R,6R)—HNK enantiomer exertsbehavioral, electroencephalographic, electrophysiological and cellularantidepressant-related actions in mice. Zanos et al., Nature 2016, 533,481-486. These results underscore favorable physiochemical propertiesfor HNK that are pertinent in the development of rapid acting agents indepression with particular importance to treatment-resistant depressivedisorders and depressive disorders with suicidal ideation. See, e.g.,DiazGranados et al., J Clin Psychiatry 2010, 71, 1605-1611; Cusin etal., Am. J. Psych. 2012, 169, 868-869; Larkin et al., Int. J.Neuropsych. 14, 1127-1131; Abdallah et al., Depress. Anxiety 2016, 33,689-697.

Obsessive Compulsive Disorders

In some embodiments, the disclosure provides methods of treating anobsessive-compulsive disorder (OCD). Without being limited bymechanisms, several lines of neurochemical and genetic evidence suggestthat glutamate dysregulation may contribute to obsessive-compulsivedisorder (OCD) and that targeting glutamate may be beneficial intreating refractory disease. Kariuki-Nyuthe et al., Curr. Opin. Psych.2014, 27, 32-37; Rodriguez et al., Neuropsychopharmacology. 2013, 38,2475-2483; Pittenger, Psychiatr. Ann. 2015, 45, 308-315. OCD may theretherefore be amenable to treatment by modulators of glutamate signaling,which can include chemical entities of the present disclosure.

Accordingly, in certain embodiments, the disclosure provides methods fortreating OCD, comprising administering to a subject in need thereof aneffective amount of a chemical entity of Formula (I) or composition ofthe present disclosure. In a specific aspect, the chemical entity is acompound of Formula (I), or a pharmaceutically acceptable salt thereof.

Anxiety

In some embodiments, the disclosure provides methods of treating ananxiety disorder, comprising administering to a subject in need thereofan effective amount of a chemical entity of Formula (I) or compositionof the present disclosure. In a specific aspect, the chemical entity isa compound of Formula (I), or a pharmaceutically acceptable saltthereof.

In a specific embodiment, chemical entities, including compounds, of thepresent disclosure are used as anti-anxiety (anxiolytic) agents to treatan anxiety disorder.

Bipolar Disorders

In some embodiments, the disclosure provides methods of treating abipolar disorder, comprising administering to a subject in need thereofan effective amount of a chemical entity of Formula (I) or compositionof the present disclosure. In a specific aspect, the chemical entity isa compound of Formula (I), or a pharmaceutically acceptable saltthereof.

In a specific embodiment, the bipolar disorder is bipolar I disorder,bipolar II disorder, cyclothymic disorder, or other bipolar and relateddisorders.

Trauma- and Stressor-Related Disorders

In some embodiments, the disclosure provides methods of treating trauma-and stressor-related disorders, comprising administering to a subject inneed thereof an effective amount of a chemical entity of Formula (I) orcomposition of the present disclosure. In a specific aspect, thechemical entity is a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof. Trauma- and stressor-related disorders involveexposure to a traumatic or stressful event. See, e.g., Zhang et al.,Psychopharmacology 2015, 232, 663-672. In one embodiment, the disorderis post-traumatic stress disorder (PTSD), including chronic PTSD. See,e.g., Feder et al., JAMA Psychiatry 2014, 71, 681-688. In anotherembodiment, the disorder is acute stress disorder (ASD).

In some embodiments, the disclosure provides methods of treating pain.For example, sub-anesthetic does of (R,S)-ketamine have demonstratedefficacy in treating neuropathic and chronic pain, including thetreatment of patients suffering from complex regional pain syndrome(CRPS). Goldberg et al., Pain Physician 2010, 13, 379-387. Moreover,analysis of plasma samples obtained from CRPS patients receiving(R,S)-ketamine as a 5-day continuous infusion reveals that the primarydrug, (R,S)-ketamine, is not primarily responsible for the therapeuticresponse and instead that the active agents responsible for thetherapeutic response may include HNK metabolites. Moaddel et al.,Talanta 2010, 15, 1892-1904. More generally, ketamine may be useful asan effective analgesic in treating postoperative pain, chronic pain,intractable cancer pain, uncontrolled severe pain, acute and subacutepain in opioid-tolerant patients, and pain in palliative care patients.See, e.g., Hirota and Lambert, Br. J. Anaesth. 2001, 107, 123-126;Lossignol et al., Support Care Cancer 2005, 13, 188-93; Chazan et al.,J. Opioid Manag. 2008, 4, 173-180; Carstensen and Møllerand, Br. J.Anaesth. 2010, 104, 410-406; Beaudoin et al., Acad. Emerg. Med. 2014,11, 1193-1202.

Accordingly, in certain embodiments, the disclosure provides methods fortreating pain, comprising administering to a subject in need thereof aneffective amount of a chemical entity of Formula (I). In a specificaspect, the chemical entity is a compound of Formula (I), or apharmaceutically acceptable salt thereof.

In some embodiments, an effective amount is an amount effective todecrease painful symptoms, wherein a decrease in painful symptom is atleast a 50% reduction of painful symptoms on a pain rating scale.

In some embodiments, pain is associated with a neurological disorder. Inparticular embodiments, pain is associated with complex regional painsyndrome (CRPS). In some embodiments, pain is associated with chronicfatigue syndrome or fibromyalgia, and may include muscle pain,myofascial pain, temporal summation, and referred pain. See, e.g.,Graven-Nielsen et al., Pain. 2000, 85, 483-491; Bennett, Curr. Opin.Rheumatol. 1998, 10, 95-103.

In some embodiments, the pain is chronic pain, acute pain, subacutepain, neuropathic pain, post-operative pain, cancer pain, inflammatorypain, visceral pain, migraine pain, headache, and menstrual pain. In aspecific embodiment, the pain is migraine pain. See, e.g., Kaube et al.,Neurology 2000, 55, 139-141. In a specific embodiment, the pain is aheadache, including a cluster headache. See, e.g., Krusz et al., J. Pain2010, 11, S₄₃; Granata et al., Schmerz 2016, 30, 286-288. In a specificembodiment, the pain is menstrual pain. See, e.g., U.S. Patent Appl. No.2015-0313892; Udoji and Ness, Pain Manag. 2013, 3, 387-394.

Other Indications

Studies have reported that glutamate receptor subunits are expressed incells found in many different tumors and cancers, such as glioma,colorectal and gastric cancer, oral squamous cell carcinoma, prostatecancer, melanoma, and osteosarcoma. See, e.g., Stepulak et al.,Histochem. Cell Biol. 2009, 132, 435-445. Accordingly, in certainembodiments, the disclosure provides methods for treating cancer,comprising administering to a subject in need thereof an effectiveamount of a chemical entity of Formula (I). In a specific aspect, thechemical entity is a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof.

Several studies indicate that ketamine action is associated withanti-inflammatory effects in vivo and in some clinical settings. See,e.g., Roytblat et al., Anesth. Analg. 1998, 87, 266-271; Mazar et al.,Anesthesiology. 2005, 102, 1174-1181; Suliburk et al., Surgery 2005,138, 134-140; De Kock et al., CNS Neurosci. Ther. 2013, 19, 403-410.Accordingly, in certain embodiments, the disclosure provides methods fortreating various inflammatory conditions, such as autoimmune, acquiredimmune, or drug-induced immune conditions, or inflammation caused byanother condition, comprising administering to a subject in need thereofan effective amount of a chemical entity of Formula (I). In a specificaspect, the chemical entity is a compound of Formula (I), or apharmaceutically acceptable salt thereof.

Studies suggest that intermittent ketamine infusions can suppresscompulsive behavior in eating disorders. See, e.g., Mills et al., QJM1998, 91, 493-503. Accordingly, in certain embodiments, the disclosureprovides methods for treating an eating disorder, comprisingadministering to a subject in need thereof a therapeutically effectiveamount of a chemical entity of Formula (I). In a specific aspect, thechemical entity is a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof.

In some embodiment, the present disclosure provides a method of treatinga seizure. See, e.g., Sheth et al., Neurology 1998, 51, 1765-1766.Accordingly, in certain embodiments, the disclosure provides methods fortreating a seizure, comprising administering to a subject in needthereof a therapeutically effective amount of a chemical entity ofFormula (I). In a specific aspect, the chemical entity is a compound ofFormula (I), or a pharmaceutically acceptable salt thereof.

Cognitive Enhancement and Performance

Chemical entities of Formula (I) are also useful in enhancing learningand memory, as well as other cognitive functions that involveglutamatergic signaling, including attention and alertness. For example,AMPA Receptor trafficking underlies numerous experience-driven phenomenathat range from forming neuronal circuits to modifying behavior. See,e.g., Kessels and Malinow, Neuron 2009, 12, 340-350; Anggono andHugnair, Curr. Opin. Neurobiol. 2012, 22, 461-469; Henley and Wilkinson,Dialogs in Clinical Neuroscience 2013, 15, 11-27.

In addition, AMPA Receptor modulation has been implicated in humancognitive performance, alertness, and recovery sleep. Boyle et al., J.Psychopharm. 2012, 26, 1047-1057; Partin, Curr. Opin. Pharmacol. 2015,20, 46-53; Hagewoud et al., J. Sleep. Res. 2010, 19, 280-288.Accordingly, in some embodiments, the disclosure provides methods ofenhancing memory and cognition, as well as treating memory and othercognitive deficits associated with normal aging and age-relatedneurological disorders, comprising administering to a subject in needthereof an effective amount of a chemical entity of Formula (I). In aspecific aspect, the chemical entity is a compound of Formula (I), or apharmaceutically acceptable salt thereof.

In other embodiments, the disclosure provides a method of modulatingsleep, comprising administering to a subject in need thereof aneffective amount of a chemical entity of Formula (I). In someembodiments, the method of modulating sleep is promoting sleep recoveryafter sleep deprivation. In a specific aspect, the chemical entity is acompound of Formula (I), or a pharmaceutically acceptable salt thereof.

In some embodiments, chemical entities of the present invention areuseful in methods (or in the manufacture of a medicament or compositionfor use in such methods) of enhancing the efficacy of cognitivebehavioral therapy (CBT) for a neurological disorder. CBT is apsychosocial intervention that is a widely used for treating mentaldisorders. See, e.g., Hofmann et al., J. Cognit. Ther. Res. 2012, 36,427-440. CBT focuses on the development of personal coping strategiesthat target solving current problems and changing unhelpful patterns incognitions (e.g., thoughts, beliefs, and attitudes), behaviors, andemotional regulation. Although originally designed to treat depression,CBT can be used for a number of neurological disorders, includingobsessive compulsive disorder, generalized anxiety disorder, and trauma-and stressor-related disorders, such as PTSD.

In some embodiments, chemical entities of the present invention areuseful in methods (or in the manufacture of a medicament or compositionfor use in such methods) of enhancing the efficacy of dialecticalbehavior therapy (DBT) for a neurological disorder. DBT is a specifictype of cognitive-behavioral psychotherapy designed to help peoplechange patterns of behavior that are not helpful, such as self-harm,suicidal thinking, and substance abuse. Since its development, it hasalso been used for the treatment of other kinds of mental healthdisorders.

Accordingly, in some embodiments, the present disclosure provides amethod of administering to a subject undergoing CBT or DBT for aneurological disorder a therapeutically effective amount of a chemicalentity of Formula (I). In a specific aspect, the chemical entity is acompound of Formula (I), or a pharmaceutically acceptable salt thereof.In a specific aspect, the neurological disorder is depression. Inanother aspect, the neurological disorder is obsessive compulsivedisorder. In another aspect, the neurological disorder is generalizedanxiety disorder. In another aspect, the neurological disorder isselected from trauma- and stressor disorders, such as PTSD.

Treatment Combinations

In some embodiments, a compound of Formula (I) is administered withanother active agent to treat an indication disclosed herein. Inspecific embodiments, the combination is administered to treatdepression, schizophrenia, Alzheimer's disease, migraine variants withor without pain, Lou Gehrig's disease (also called amyotrophic lateralsclerosis or ALS), or pain. Such administration may be simultaneously orsequentially.

Exemplary agents for treating depression include selective serotoninreuptake inhibitors (SSRIs), such as sertraline, fluoxetine, citalopram,escitalopram, paroxetine, fluvoxamine, and trazodone; serotonin andnorepinephrine reuptake inhibitors (SNRIs), such as desvenlafaxine,duloxetine, levomilnacipran, and venlafaxine; tricyclic antidepressants(TCAs), such as amitriptyline, amoxapine, clomipramine, desipramine,doxepin, imipramine, nortriptyline, protriptyline, and trimipramine;monoamine oxidase inhibitors (MAOIs), such as isocarboxazid, phenelzine,selegiline, and tranylcypromine; and other classes of drugs, such asmaprotiline, bupropion, vilazodone, nefazodone, trazodone, vortioxetine,and mirtazapine.

Exemplary agents for treating schizophrenia include: clozapine,aripiprazole, brexpiprazole, cariprazine, lurasidone, paliperidone,quetiapine, risperidone, olanzapine, ziprasidone, and iloperidone.

Exemplary agents for treating Alzheimer's Dementia include, but are notlimited to, donepezil, rivastigmine, galantamine, marijuana-likecannabinoids, and memantine.

Exemplary agents for treating Migraines include, but are not limited to,caffeine; acetaminophen; nonsteroidal anti-inflammatory drugs (NSAIDs),such as aspirin, ibuprofen, naproxen, ketoprofen, tolmetin, etodolac,nabumetone, piroxicam, and droxican; cyclo-oxygenease-2 (Cox-2)inhibitors such as celcoxib; topiramate; amitriptyline; sumatriptan;frovatriptan; rizatriptan; naratriptan; almotriptan; eletriptan;botulinum toxin; narcotic pain medications such as codeine, fentanyl,hydrocodone, hydromorphone, meperidine, methadone, morphine, andoxycodone; centrally acting analgesics, such as tramadol; and otherclasses of drugs, such as certain anticonvulsants, antidepressants,psychostimulants, marijuana-like cannabinoids, and corticosteroids.

Exemplary agents for treating ALS include riluzole.

Exemplary agents for treating pain include, but are not limited to,acetaminophen; nonsteroidal anti-inflammatory drugs (NSAIDs), such asaspirin, ibuprofen, naproxen, ketoprofen, tolmetin, etodolac,nabumetone, piroxicam, and droxican; cyclo-oxygenease-2 (Cox-2)inhibitors such as celcoxib; narcotic pain medications such as codeine,fentanyl, hydrocodone, hydromorphone, meperidine, methadone, morphine,and oxycodone; centrally acting analgesics, such as tramadol; and otherclasses of drugs, such as certain anticonvulsants, antidepressants,psychostimulants, marijuana-like cannabinoids, and corticosteroids.

The preceding list of additional active agents is meant to be exemplaryrather than fully inclusive. Additional active agents not included inthe above list may be administered in combination with a compound ofFormula (I). The additional active agent will be dosed according to itsapproved prescribing information, though in some embodiments theadditional active agent will be dosed at less the typically prescribeddose and in some instances less than the minimum approved dose.

EXAMPLES

The present disclosure is further illustrated by the followingnon-limiting Examples. These Examples are understood to be exemplaryonly, and they are not to be construed as limiting the scope of thepresent disclosure.

Exemplary compounds can be described by reference to the illustrativesynthetic schemes for their general preparation below and the specificexamples to follow.

One skilled in the art will recognize that, to obtain the variouscompounds herein, starting materials may be suitably selected so thatthe ultimately desired substituents will be carried through the reactionscheme with or without protection as appropriate to yield the desiredproduct. Alternatively, it may be necessary or desirable to employ, inthe place of the ultimately desired substituent, a suitable group thatmay be carried through the reaction scheme and replaced as appropriatewith the desired substituent. Unless otherwise specified, the variablesare as defined above in reference to Formula (I). Reactions may beperformed between −100° C. and the reflux temperature of the solvent.Reactions may be heated employing conventional heating or microwaveheating. Reactions may also be conducted in sealed pressure vesselsabove the normal reflux temperature of the solvent.

Synthetic Schemes

In accordance with Scheme A, hydroxylimine compounds can undergo athermal rearrangement to give 2-aminocyclohexanones when heated in thepresence of a heat transfer fluid such as Dowtherm-A at temperaturesranging from 100 to 240° C.

Subsequent halogenation, under conditions known to one skilled in theart, provides the haloketone. For example, treatment of compounds offormula (II) with bromine in 48% hydrobromic acid at temperaturesranging from 40 to 100° C. affords bromoketones of formula (III) as thehydrobromide salt.

Subsequent dehalogenation under basic conditions known to one skilled inthe art affords the enone. For example, treatment of compounds offormula (III) in the presence of a base such as DBN, DBU and the like,in a solvent such as ACN, at reflux, affords compounds of formula (IV).

In accordance with Scheme B, compounds of formula (IX) can besynthesized in five steps from a compound of formula (II):

Treatment of compounds of formula (II) with an alkyl chloroformate,under basic conditions known to one skilled in the art, providescompounds of formula (V). For instance, treatment of the2-aminocyclohexanone of formula (II) with methyl chloroformate in thepresence of a base, such as Na₂CO₃ or the like, in a solvent such abenzene, toluene, or the like, at temperatures ranging from 65-110° C.,affords the methyl carbamate of formula (V).

Subsequent treatment with a base, such as LDA or the like, followed by asilylating agent such as TMSCl, or the like, in a solvent, such as THF,and at temperatures between −78° C. and 22° C. affords the correspondingtrimethylsilyl enol ether.

Oxidation with an oxidizing agent, such as mCPBA, in the presence of abase, such as Na₂CO₃, and a solvent, such as hexanes, at roomtemperature affords the hydroxyketone of formula (VII).

Subsequent treatment with BSTFA in the presence of a base, such aspyridine or the like, in a solvent, such as DCM, chloroform or the like,at temperatures ranging from 30 to 80° C. affords the trimethylsilylether.

Deprotection of the carbamate protecting group and of the trimethylsilylether affords compounds of formula (IX). For example, treatment oftrimethylsilyl ether (VIII) with TMSI in a solvent, such as DCM,chloroform or the like, and methanol at room temperature affords theamino alcohol of formula (IX).

In accordance with Scheme C, imidates of Formula (XI) can be synthesizedin two steps from a 2-amino-6-bromocyclohexanone of formula (III):

Treatment of compounds of formula (III) with an acid chloride in thepresence of a base, under conditions known to one skilled in the art,provides compounds of formula (X). Alternatively, treatment of the2-amino-6-bromocyclohexanone with a carboxylic acid and a couplingreagent, in the presence of a base, under conditions known to oneskilled in the art, also provides the amide of formula (X). For example,treatment of compounds of formula (III) with an acid chloride, in thepresence of a base, such as TEA or the like, in a solvent such aschloroform, DCM or the like affords an amide of formula (X).

Subsequent treatment with a base, such as NaH or the like, in a solventsuch as DMF, DMA or the like, affords an imidate of formula (XI),wherein, R^(a)═—H, —C₁₋₆alkyl, —C₁₋₆haloalkyl, —C₃₋₈alkenyl,—C₃₋₈alkynyl, —(CH₂)_(n)aryl, —(CH₂)_(n)heteroaryl,—(CH₂)_(n)cycloalkyl, —(CH₂)_(n)heterocycloalkyl, —COR², —CONR³R⁴,—CR⁵R⁶NR⁷R⁸, —CHR⁹R¹⁰, or —C(OH)R¹¹R¹².

In accordance with Scheme D, imidates of Formula (XI) can be synthesizedin three steps from a 6-aminocyclohex-2-enone of Formula (IV):

Treatment of compounds of formula (IV) with an acid chloride in thepresence of a base, under conditions known to one skilled in the art,provides the amide of Formula (XII). Alternatively, treatment of the6-aminocyclohex-2-enone with a carboxylic acid and a coupling reagent,in the presence of a base, under conditions known to one skilled in theart, also provides the amide of Formula (XII). For example, treatment ofcompounds of formula (IV) with an acid chloride, in the presence of abase, such as TEA or the like, in a solvent such as chloroform, DCM orthe like, affords an amide of formula (XII).

Subsequent treatment with a halogenation reagent, such as NIS or thelike, in the presence of a base, such as Et3N or the like, in a solvent,such as DCM or chloroform, affords the iodinated imidate of formula(XIII).

Subsequent treatment with Bu3SnH in a solvent, such as DCM or the like,at temperatures ranging from 20 to 60° C. provides an imidate of formula(XI), wherein, R^(a)═—H, —C₁₋₆alkyl, —C₁₋₆haloalkyl, —C₃₋₈alkenyl,—C₃₋₈alkynyl, —(CH₂)_(n)aryl, —(CH₂)_(n)heteroaryl,—(CH₂)_(n)cycloalkyl, —(CH₂)_(n)heterocycloalkyl, —COR², —CONR³R⁴,—CR⁵R⁶NR⁷R⁸, —CHR⁹R¹⁰, or —C(OH)R¹¹R¹².

In accordance with Scheme E, imidates of Formula (XI) can be synthesizedin two steps from a 2-amino-6-hydroxy-cyclohexanone of Formula (IX).

Treatment of compounds of formula (IX) with an acid chloride in thepresence of a base, under conditions known to one skilled in the art,provides the amide of Formula (XIV). Alternatively, treatment of the2-amino-6-hydroxycyclohexanone derivative with a carboxylic acid and acoupling reagent, in the presence of a base, under conditions known toone skilled in the art, also provides the amide of Formula (IX). Forexample, treatment of the2-amino-6-hydroxy-2-(2-chlorophenyl)cyclohexanone of Formula (IX) withan acid chloride, in the presence of a base, such as TEA or the like, ina solvent such as chloroform, DCM or the like affords an amide offormula (XIV).

Subsequent treatment with ethylene glycol in the presence of a base,such as NaOH or the like, at temperatures ranging from 150-220° C.provides an imidate of formula (XI), wherein, R^(a)═—H, —C₁₋₆alkyl,—C₁₋₆haloalkyl, —C₃₋₈alkenyl, —C₃₋₈alkynyl, —(CH₂)_(n)aryl,—(CH₂)_(n)heteroaryl, —(CH₂)_(n)cycloalkyl, —(CH₂)_(n)heterocycloalkyl,—COR², —CONR³R⁴, —CR⁵R⁶NR⁷R⁸, —CHR⁹R¹⁰, or —C(OH)R¹¹R¹². Alternatively,heating intermediates of formula (XIV) at a temperature ranging between180-250° C. and a pressure less than 0.5 mmHg for a period of 1-5 h,followed by cooling to room temperature then treatment with a solutionof tetraethylammonium hydroxide in a solvent, such as DCM or the like,then subsequent removal of solvent and heating again at reduced pressureas previously described, affords imidate compounds of formula (XI).

In accordance with Scheme E, deprotection of a nitrogen protecting groupis performed under the appropriate conditions known to one skilled inthe art, depending on which protecting group is used. In one instance,deprotection of carbamate intermediates of formula (XV), wherein thecarbamate protecting group is 9-fluorenylmethyl carbamate (Fmoc),2-trimethylsilylethyl carbamate (TeOC), t-butyl carbamate (Boc), allylcarbamate (Alloc), benzyl carbamate (Cbz) or the like, can be achievedunder conditions known to one skilled in the art. For example, FMCdeprotection with piperidine provides a compounds of formula (XVI),wherein each R^(b) independently=—H, -halo, —NH₂, —C₁₋₈alkyl,—C₁₋₈haloalkyl, —(CH₂)_(n)CONH₂, —(CH₂)_(n)COOH, —(CH₂)_(n)aryl,—(CH₂)_(n)heteroaryl, —(CH₂)_(n)cycloalkyl, and —(CH₂)_(n)heterocycloalkyl, each optionally substituted, wherein n isindependently an integer selected from 0, 1, 2, 3, and 4; and R^(c)═—H,—C₁₋₄alkyl, and —C₁₋₄haloalkyl. Alternatively, deprotection ofsulfonamide intermediates of formula (XV), wherein the sulfonamideprotecting group is p-toluenesulfonyl (Ts), trifluoromethanesulfonyl,trimethylsilylethanesulfonamide (SES), tert-butylsulfonyl (Bus) or thelike, can be achieved under conditions known to one skilled in the art.For example, treatment of a Ts protected compound of formula (XV) with astrong acid, such as HBr or the like, in a solvent, such as acetic acidor the like, provides a compound of formula (XVI), wherein R^(b) andR^(c) are described above.

Chemistry:

In some embodiments, the following experimental and analyticalprotocols, unless otherwise indicated, can be used to obtain theresulting compounds.

Unless otherwise stated, reaction mixtures are magnetically stirred atroom temperature (rt) under an atmosphere of nitrogen. Where solutionsare “dried,” they are generally dried over a drying agent such as Na₂SO₄or MgSO₄. Where mixtures, solutions, and extracts are “concentrated,”they are typically concentrated on a rotary evaporator under reducedpressure.

Reactions under microwave irradiation conditions are carried out in aCEM Discover-SP with Activent microwave reaction apparatus, model number909150, or Biotage Initiator, model number 355302.

Normal-phase flash column chromatography (FCC) is performed on Silica(SiO₂) using packed or prepackaged cartridges, eluting with theindicated solvents.

Analytical LC/MS is obtained on a Waters 2695 Separations Unit, 2487Dual Absorbance Detector, Micromass ZQ fitted with ESI Probe, or aWaters Acquity™ Ultra performance LC (UPLC) with PDA eX and SQdetectors. Alternatively, LC-MS is performed on a Waters Acquity UPLC-MSinstrument equipped with a Acquity UPLC BEH C₁₈ column (1.7 μm, 2.1×50mm) and the solvent system A: 0.1% HCOOH in H₂O and B: 0.1% HCOOH inACN. Column temperature is 45° C.

Analytical SFC-MS is performed on a Waters UPC²-MS instrument equippedwith a Acquity UPC² BEH 2-ethylpyridine column (1.7 μm, 2.1×50 mm) andthe solvent system A: CO₂ and B: 0.1% NH₄OH in MeOH. Column temperatureis 55° C. All compounds are run using the same elution gradient, i.e.,3% to 35% solvent B in 0.75 min with a flow rate of 2.5 mL/min.

Preparative HPLC is performed on a Shimadzu SIL-10AP system using aWaters SunFire™ OBD 30 mm×100 mm×2.5 μm (particle size) C¹⁸ column witha 15-minute gradient of 10-100% acetonitrile in water and 0.05%trifluoroacetic acid added as a modifier to both phases. Elutionprofiles are monitored by UV at 254 and 220 nm. Alternatively,preparative HPLC is performed on a Waters Fractionlynx system equippedwith a XBridge Prep C₁₈ OBD column (5 μm, 19×50 mm) and the solventsystem: H₂O:ACN and 2% TFA in H₂O. Specific elution gradients are basedon retention times obtained with an analytical UPLC-MS, however, ingeneral all elution gradients of H₂O and ACN are run over a 5.9 min runtime with a flow rate of 40 mL/min. An autoblend method is used toensure a concentration of 0.1% TFA throughout each run.

Preparative SFC-MS is run on a Waters Prep100 SFC-MS system equippedwith a Viridis 2-ethylpyridine OBD column (5 μm, 30×100 mm) and thesolvent system: CO₂:MeOH and 1% NH₄OH in MeOH. Specific elutiongradients are based on retention times obtained with an analyticalUPC²-MS; however, in general all elution gradients of CO₂ and MeOH arerun over a 3.6 min run time with a flow rate of 100 mL/min and a columntemperature of 55° C. An autoblend method is used to ensure aconcentration of 0.2% NH₄OH throughout each run.

Nuclear magnetic resonance (NMR) spectra can be obtained in a Varian 400MHz or Bruker 400 MHz NMR.

Chemical names can be generated using ChemBioDraw Ultra 12.0(CambridgeSoft Corp., Cambridge, Mass.) or ChemAxon (Budapest, Hungary).

Intermediate 1. 2-amino-6-bromo-2-(2-chlorophenyl)cyclohexanoneHydrobromide

This compound may be prepared in the manner described in J. Org. Chem.,1981, 46, 5055-5060, for example, in accordance with the following:

Step 1. 2-Amino-2-(2-chlorophenyl)cyclohexanone. A solution of 655 g(2.93 mol) of 1-((2-chlorophenyl)(imino)methyl)cyclopentanol in 750 mLof i-PrOH is saturated with anhydrous HCl and then diluted to 1.5 L withanhydrous Et₂O. The crystals that form are removed by filtration anddried to give 1-((2-chlorophenyl)(imino)methyl)cyclopentanol as thehydrochloride salt. To 3 L of Dowtherm-A at 200° C. is added 379 g (1.46mol) of 1-((2-chlorophenyl)(imino)methyl)cyclopentanol (hydrochloridesalt) which causes the temperature to fall to 180° C., where it ismaintained for 7 min. The reaction mixture is cooled to 10° C., and thesolid is removed by filtration and dissolved in H₂O. The filtrate isdiluted to 3 L with Et₂O and extracted with H₂O. The combined aqueousfractions are washed with Et₂O, made basic with 50% aqueous NaOH, andextracted with Et₂O. The ether layer is washed with water, dried,de-colorized with charcoal, filtered through Celite, and concentrated.The residue is distilled to give the title compound.

Step 2: 2-Bromo-6-amino-6-(2-chlorophenyl)cyclohexanone Hydrobromide. Asolution of 298 g (1.33 mol) of 2-Amino-2-(2-chlorophenyl)cyclohexanonein 1.2 L of 48% aqueous HBr is heated to 70° C., and 216 g (1.35 mol) ofbromine is added dropwise. The mixture is stirred for 10 min after theaddition is complete and cooled to 5° C. The crystals are removed byfiltration, washed copiously with acetone, and dried to give 408 g ofthe title compound, mp 142-145° C. A second crop (30 g, mp 142-145° C.)is obtained by decolorizing and concentrating the acetone washes. An NMRis run in D₂O and shows the presence of excess protons in the HOD peak.The entire yield of 441 g is azeotroped in 500 mL of xylene, with therecovery being 420 g (82%; mp 209-210° C.) and the water collected in aDean-Stark trap corresponding to a monohydrate.

Intermediate 2. 1-amino-2′-chloro-5,6-dihydro-2(1H)-one Hydrobromide

This compound may be prepared in the manner described in J. Org. Chem.,1981, 46, 5055-5060, for example, in accordance with the following:

6-Amino-6-(2-chlorophenyl)-2-cyclohexen-1-one. A solution of 35 g (0.28mol) of 1,5-diazabicyclo[3.3.1]non-5-ene, 200 mL of acetonitrile, and 74g (0.25 mol) of 2-Bromo-6-amino-6-(2-chlorophenyl)cyclohexanone (freebase) is refluxed for 20 h. The solvent is evaporated and the residuediluted with ether and 5% aqueous NaOH. The layers are separated, andthe organic layer is extracted with 5% aqueous HCl. The combinedacid-water layers are decolorized with charcoal, filtered throughCelite, and made basic with 50% aqueous NaOH. The crystallineprecipitate is removed by filtration, is washed with water, and is driedto give 31 g (57%) of the title compound, mp 120-123° C.

Intermediate 3. 2-amino-2-(2-chlorophenyl)-6-hydroxycyclohexanone

This compound may be prepared in the manner described in J. Med. Chem.,1986, 29, 2396-2399, for example, in accordance with the follows:

Step 1. 2-(o-Chlorophenyl)-2-[(methoxycarbonyl)-aminocyclohexanone. To amixture of 2-amino-2-(2-chlorophenyl)cyclohexanone (3.0 g, 14 mmol) inanhydrous benzene (100 mL) and Na₂CO₃ (4.5 g) is added a solution ofmethyl chloroformate (3.0 mL, 40 mmol) in anhydrous benzene (10 mL).After heating under reflux for 3 h, the reaction mixture is cooled toroom temperature and washed in turn with H₂O, 10% Na₂CO₃, and H₂O again.The product is diluted with either, dried (MgSO₄), and concentratedunder reduced pressure, wherein the title compound precipitates as awhite solid.

Step 2.2-(o-Chlorophenyl)-2-[(methoxycarbonyl)amino]-6-hydroxycyclohexanone. Toa cooled (0° C.) mixture of diisopropylamine (4 mL, 28 mmol) and dry THF(30 mL) is added a solution of n-butyllithium in hexane (1.6 M, 17 mL,28 mmol). The reaction mixture is stirred at 0° C. for 1 h, cooled to−78° C., and treated dropwise with a solution of2-(o-Chlorophenyl)-2-[(methoxycarbonyl)-aminocyclohexanone (3.2 g, 11mmol) in dry THF (20 mL). After stirring for a period of 2 h, Me₃SiCl (4mL, 28 mmol) is added, and the reaction mixture is stirred for 20 minbefore warming to room temperature over 45 min. Hexane is then added,and the resulting solution is washed with 10% NaHCO₃ and H₂O and dried(MgSO₄), and the solvent is removed in vacuo to afford the crude productas a yellow oil. Purification by column chromatography on silica gel (75g, 70-325 mesh, EtOAc as eluent) gives methyl(2′-chloro-6-((trimethylsilyl)oxy)-1,2,3,4-tetrahydro-[1,1′-biphenyl]-1-yl)carbamateas a clear yellow oil, yield 4.5 g (100%). To a mixture of methyl(2′-chloro-6-((trimethylsilyl)oxy)-1,2,3,4-tetrahydro-[1,1′-biphenyl]-1-yl)carbamate(4.46 g, 12.6 mmol) in hexane (60 mL) and Na₂CO₃ (2.5 g) is added mCPBA(4.5 g, 20.8 mmol). The reaction mixture is stirred at room temperaturefor 3 h, and the product is washed (10% Na₂SO₃, then H₂O), dried(MgSO₄), and evaporated to give a white solid. Column chromatography onsilica gel (75 g, 70-325 mesh, 5% CH₃CN in CH₂C1₂ as eluent) gives thetitle compound as an oil.

Step 3. 2-(o-Chlorophenyl)-2-amino-6-hydroxycyclohexanone(6-Hydroxynorketamine). To a solution of2-(o-Chlorophenyl)-2-[(methoxycarbonyl)amino]-6-hydroxycyclohexanone(3.5 g, 12 mmol) in anhydrous CH₂C1₂ (80 mL) is added BSTFA (4 mL, 15mmol) and dry pyridine (0.2 mL). The mixture is heated under reflux for1 h, and excess reagents are removed in vacuo to give methyl(1-(2-chlorophenyl)-2-oxo-3-((trimethylsilyl)oxy)cyclohexyl)carbamate asa white solid: A solution of methyl(1-(2-chlorophenyl)-2-oxo-3-((trimethylsilyl)oxy)cyclohexyl)carbamate(4.5 g, 12 mmol) in dry CH₂C1₂ (80 mL) is treated dropwise with Me₃SiI(3 mL, 17 mmol), and the resulting mixture is stirred at roomtemperature for 30 min. Methanol (80 mL) is then added, the mixture iswashed (10% Na₂SO₃, then H₂O) and dried (Na₂SO₄), and the solvent isevaporated to give the crude product as a yellow oil (1.0 g). Columnchromatography on silica gel (10 g, 70-325 mesh, EtOAc as eluent) givesthe title compounds as a pure oil.

Intermediate 4. N-(3-bromo-1-(2-chlorophenyl)-2-oxocyclohexyl)formamide

To a suspension of 2-amino-6-bromo-2-(2-chlorophenyl)cyclohexanonehydrobromide (Intermediate 1, 1.0 equiv) in DMF (0.2 M) is added DIEA (3equiv.), HATU (1.2 equiv) and formic acid (1.5 equiv.) then the reactionmixture is stirred at room temperature for 2 h, and then the reaction isquenched with a saturated solution of NaHCO₃. The aqueous layer isextracted with EtOAc (3×). The combined organic layer is dried (Na₂SO₄)and evaporated. The residue is purified to give the title compound.

Intermediate 5.(1S,5R,8S)-5-(2-chlorophenyl)-8-iodo-3-(1-((4-methoxybenzyl)oxy)ethyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one

This compound may be prepared by methods known in the art, such as thatdescribed in Molecules, 2011, 16, 7691-7705.

Step 1. To a suspension of1-amino-2′-chloro-5,6-dihydro-[1,1′-biphenyl]-2(1H)-one hydrobromide(Intermediate 2, 1.0 equiv.) in CHCl₃ (0.26 M) is added Et₃N (2 equiv.)and 2-((4-methoxybenzyl)oxy)propanoyl chloride (1.15 equiv.) and thereaction mixture is stirred at room temperature for 2 h, and then washedwith H₂O two times. The aqueous layer is extracted with EtOAc threetimes. The combined organic layer is dried (Na₂SO₄) and evaporated, andthe residue is recrystallized to giveN—((R)-2′-chloro-6-oxo-1,2,3,6-tetrahydro-[1,1′-biphenyl]-1-yl)-2-((4-methoxybenzyl)oxy)propanamide.

Step 2. A solution of N—((R)-2′-chloro-6-oxo-1,2,3,6-tetrahydro-[1,1′-biphenyl]-1-yl)-2-((4-methoxybenzyl)oxy)propanamide (1.0 equiv) inCH₂C1₂ (0.13 M) is treated with NIS (1.0 equiv) and subsequently stirredfor 14 h at room temperature. When the reaction is complete, the mixtureis washed with 10% NaOH solution three times. The aqueous solution isextracted with CH₂Cl₂ three times and the combined organic phase isdried (Na₂SO₄) and evaporated to give the title compound.

Intermediate 6.N-(1-(2-chlorophenyl)-3-hydroxy-2-oxocyclohexyl)acetamide

This compound may be prepared in a manner analogous to that described inJ. Med. Chem, 2007, 50, 5311-5323, for example, as follows.

To a solution of 2-amino-2-(2-chlorophenyl)-6-hydroxycyclohexanone(Intermediate 3, 1.0 equiv) in methanol (0.05 M) is added aceticanhydride (1.1 equiv.) and the reaction mixture is stirred at roomtemperature for 4 h. Upon completion of the reaction, the solution isneutralized with a 10% sodium bicarbonate solution (pH=8) then madebasic with a 10% ammonia solution (pH=10). The organic layer isextracted with dichloromethane, washed with brine, dried (Na₂SO₄) andthen the solvent is evaporated. The crude residue is purified by columnchromatography to give the title compound.

Example 1.(1R,5R)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one

This compound may be prepared in a manner analogous to that described inJ. Org. Chem., 2007, 72, 8656-8670, J. Org. Chem., 2011, 76, 680-683,and Org. Lett., 2016, 18, 948-951, for example, as follows.

A solution of N-(3-bromo-1-(2-chlorophenyl)-2-oxocyclohexyl)formamide(Intermediate 4, 1.0 equiv) in dry DMF (0.06 M) is treated with NaH (1.0equiv) at 0° C. The reaction mixture is stirred at 0° C. for 15 min andthen at room temperature until TLC or LCMS reveals the disappearance ofthe starting material. Next, the reaction mixture is quenched with H₂Oand extracted three times with Et₂O. The combined organic layers arewashed with H₂O three times and dried over Na₂SO₄. Flash chromatographyon silica gel affords the desired compound.

Example 2. (1R,5R)-5-(2-chlorophenyl)-3-(1-hydroxyethyl)-2-oxa-4azabicyclo[3.3.1]non-3-en-9-one

This compound may be prepared in a manner analogous to that described inMolecules, 2011, 16, 7691-7705, as follows.

Step 1. Bu₃SnH (2.1 equiv.) is added to a solution of(1S,5R,8S)-5-(2-chlorophenyl)-8-iodo-3-(1-((4-methoxybenzyl)oxy)ethyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one(Intermediate 5, 1.0 equiv) in dry CH₂Cl₂ (0.1 M) under Ar. Afterstirring for 20 h at 40° C., the solvent is evaporated off and theresidue is purified by column chromatography on silica gel(n-hexane:EtOAc 10:1) to afford(1R,5R)-5-(2-chlorophenyl)-3-(14(4-methoxybenzyl)oxy)ethyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one.

Step 2. To a solution of(1R,5R)-5-(2-chlorophenyl)-3-(14(4-methoxybenzyl)oxy)ethyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one(1.0 equiv) in a mixture of dichloromethane/water (100:1, 0.06 M) at 0°C. is added DDQ (1.2 equiv) and the resulting mixture is stirred at roomtemperature for several hours. Upon completion of the reaction, thereaction mixture is washed with a 40% aqueous sodium hydrogencarbonatesolution, followed by brine. The organic layer is dried (Na₂SO₄) andsolvent is removed under reduced pressure. The crude product is purifiedto give the title compound.

Example 3.(1R,5R)-5-(2-chlorophenyl)-3-methyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one

This compound may be prepared in a manner analogous to that described inJ Med. Chem., 2007, 50, 5311-5323, as follows.

Step 1. To a suspension ofN-(1-(2-chlorophenyl)-3-hydroxy-2-oxocyclohexyl)acetamide (Intermediate6, 1.0 equiv) in freshly distilled ethylene glycol (0.02 M) is addedsodium hydroxide (0.2 equiv). After heating at 215° C. for 6 h, themixture is then made basic with a 10% ammonia solution (pH=10) andextracted with dichloromethane. The organic layer is dried over Na₂SO₄and filtered, and the solvent is evaporated to give the title compound.

The compounds of Examples 4-61, corresponding to the (1R,5R)enantiomers, may each be prepared in a manner analogous to those ofExamples 1-3, with appropriate starting material substitutions andprotection or deprotection steps as would be appreciated by those ofskill in the art. In addition, the corresponding (1S,5S) enantiomers ofExamples 1-61 can be synthesized in a manner similar to that describedusing the appropriate starting material substitutions and syntheticprocedures as known to one skilled in the art.

Example 4.(1R,5R)-3-((S)-1-amino-2-methylpropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one

Example 5.(1R,5R)-3-(aminomethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one

Example 6.(1R,5R)-5-(2-chlorophenyl)-3-fluorocarbonyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one

Example 7.(1R,5R)-5-(2-chlorophenyl)-3-((S)-1,5-diaminopentyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one

Example 8.(1R,5R)-3-((S)-1-aminoethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one

Example 9.(1R,5R)-5-(2-chlorophenyl)-3-phenyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one

Example 10.(1R,5R)-3-((1S,2R)-1-amino-2-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one

Example 11.(1R,5R)-3-((S)-1-amino-3-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one

Example 12.(1R,5R)-3-((S)-1-amino-2-phenylethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one

Example 13.(1R,5R)-3-((S)-1-amino-2-(4-hydroxyphenyl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one

Example 14.(1R,5R)-3-((S)-1-amino-2-(1H-indol-3-yl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one

Example 15.(1R,5R)-3-((S)-1-amino-2-(1H-imidazol-4-yl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one

Example 16.(1R,5R)-5-(2-chlorophenyl)-3-(pyrrolidin-2-yl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one

Example 17.(S)-3-amino-3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)propanoicAcid

Example 18.(S)-4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)butanoicAcid

Example 19.(S)-4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)butanamide

Example 20.(S)-3-amino-3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)propanamide

Example 21.(1R,5R)-3-((S)-1-amino-3-(methylthio)propyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one

Example 22.(1R,5R)-3-((R)-1-amino-2-mercaptoethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one

Example 23.(1R,5R)-3-((S)-1-amino-2-hydroxyethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one

Example 24.(1R,5R)-3-((S)-1-amino-2-methoxyethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one

Example 25.1-((S)-4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)butyl)guanidine

Example 26.(1R,5R)-5-(2-chlorophenyl)-3-ethyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one

Example 27.3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)-2-hydroxypropanoicAcid

Example 28.2-(((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)methyl)-2-hydroxysuccinicAcid

Example 29.5-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)pentanoicAcid

Example 30.3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)-2,3-dihydroxypropanoicAcid

Example 31.3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)PropanoicAcid

Example 32.(1R,5R)-5-(2-chlorophenyl)-3-heptyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one

Example 33.(1R,5R)-3-(1-amino-2-hydroselenoethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one

Example 34.(1R,5R)-5-(2-chlorophenyl)-3-(2-(methylamino)ethyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one

Example 35.(1R,5R)-5-(2-chlorophenyl)-3-(1,2-diaminoethyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one

Example 36.(1R,5R)-3-(2-amino-1-hydroxyethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one

Example 37.(1R,5R)-3-(3-aminopropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one

Example 38.(1R,5R)-3-(4-aminobutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one

Example 39.(1R,5R)-3-(3-aminopentyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one

Example 40.(1R,5R)-3-(1-amino-3-hydroxypropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one

Example 41.(1R,5R)-5-(2-chlorophenyl)-3-(1,4-diaminobutyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one

Example 42.4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)-N-ethylbutanamide

Example 43.(1R,5R)-5-(2-chlorophenyl)-3-(1,5-diamino-4-hydroxypentyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one

Example 44.1-(4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)butyl)urea

Example 45.1-(5-amino-5-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)pentyl)urea

Example 46.1-(5-amino-5-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)pentyl)guanidine

Example 47.1-(2-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)ethyl)guanidine

Example 48.(1R,5R)-3-(1-amino-2-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one

Example 49.(1R,5R)-3-(1-amino-2-(5-hydroxy-1H-indol-3-yl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one

Example 50.(1R,5R)-3-(1-amino-2-(5-methyl-1H-indol-3-yl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one

Example 51.(1R,5R)-3-(2-(1H-indol-3-yl)-1-(methylamino)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one

Example 52.(1R,5R)-5-(2-chlorophenyl)-3-(4-hydroxypyrrolidin-2-yl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one

Example 53.(1R,5R)-3-(1-amino-2-hydroxy-3-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one

Example 54.(1R,5R)-5-(2-chlorophenyl)-3-(1-(methylamino)ethyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one

Example 55.(1R,5R)-3-(2-aminopropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one

Example 56.N-(5-amino-5-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)pentyl)-3-methyl-3,4-dihydro-2H-pyrrole-2-carboxamide

Example 57.(1R,5R)-3-(1-amino-3-hydroxy-2-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one

Example 58.(1R,5R)-3-(1-amino-2,2-dimethylpropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one

Example 59.(1R,5R)-3-(amino(3-amino-4-hydroxyphenyl)methyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one

Example 60.(1R,5R)-3-(1-amino-2-hydroxy-2-phenylethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one

Example 61.(1R,5R)-3-(1-amino-2-(4-methoxyphenyl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one

Models for Evaluating Anti-Depressant Activity

In this prophetic example, animal behavioral tests known in the art areused to evaluate the antidepressant efficacy of exemplary compounds ofFormula (I). Such tests may be based on various attributes ofdepression, such as behavioral despair (e.g., Forced Swim), anxiety(e.g., Novelty Suppressed Feeding test), or exposure to uncontrollablestressors (e.g., Learned Helplessness).

Forced Swim Test

The Forced Swim Test (FST) is a widely used tool in depression researchparticularly for evaluating the acute efficacy of candidateantidepressants. In the FST, mice are placed in an inescapabletransparent tank filled with water and are evaluated for their escaperelated mobility behavior. See, e.g., Can et al., 2012, J. Vis. Exp. 59,e3638.

In some embodiments, mice are administered exemplary compounds ofFormula (I) and exhibit a longer duration of escape-directed behaviorsin the FST, compared to vehicle-administered controls.

Novelty Suppressed Feeding Test:

The Novelty Suppressed Feeding Test (NSFT) is based on the rationalethat feeding to novelty is an anxiety symptom in rodents that can beevoked by novel environmental features, including novel food, noveltesting area, and novel food containers. See, e.g., Santarelli et al.,2003, Science 301, 805-809. The test reflects the anti-anxiety effectsof antidepressants, with a response measured after administration withcandidate antidepressants.

In some embodiments, mice are administered exemplary compounds ofFormula (I) and exhibit a decreased latency to feed in the NSFT,compared to vehicle-administered controls.

Learned Helplessness:

The learned helplessness test (LHT) is based on the observation thatanimals develop deficits in escape, cognitive and rewarded behaviorswhen subjected to repeated unavoidable and uncontrollable shocks. See,e.g., J. B. Overmier and Seligman, 1967, J. Comp. Physiol. Psychol. 63,28-33; Chourbaji et al., 2005, Brain Res. Brain Res. Protoc. 16, 70-78;Zanos et al., 2016, Nature 533, 481-486.

In some embodiments, mice are administered exemplary compounds ofFormula (I) and exhibit reduced deficits in the LHT, compared tovehicle-administered controls.

Pharmacokinetic Studies

In this prophetic example, pharmacokinetic profiles of Formula (I)compounds are obtained by standard means known in the art. For example,the pharmacokinetic profiles can be obtained from animals, such asmammals, including primates (e.g., monkeys such as Rhesus Macaques(Macaca mulatta), or humans).

Comparisons between pharmaceutical compositions can be readily achievedthrough the examination of pharmacokinetic profiles and/or parametersmeasured after administration of a composition. Generally, a bloodbaseline drug concentration is obtained prior to administration.

Post-administration, blood is drawn at various time points for druganalysis. Typically, serum or plasma is isolated from the blood samplesand analyzed to determine the concentrations of the therapeutic agent.Drug concentrations in plasma (or serum) samples are analyzed by liquidchromatography-mass spectroscopy using appropriate parameters for eachcompound.

Typically, a graph is created of the time (x-axis) versus drugconcentration (γ-axis) and from this graph various pharmacokineticparameters can be derived. Alternately, the data can be entered into asoftware program that will derive the pharmacokinetic parameters and fitthem to a graph of the measured values.

Useful pharmacokinetic parameters in which to compare formulationsinclude maximal blood therapeutic concentration (Cmax), time to reachCmax (Tmax), time to reach a blood concentration of ½ of Cmax (T½), andbioavailability (BA). Typically, BA is measured by determining an areaunder the curve (AUC) of a blood therapeutic concentration versus timegraph. For comparative analysis between pharmaceutical compositions, thepharmacokinetic parameters can be compared individually, or in variouscombinations. Numerous, but non-limiting, pharmacokinetic softwareprograms can be used in practicing the teachings of the presentdisclosure, such Phoenix WinNonlin software, version 5.2.

Exemplary compounds of the present disclosure are tested for oralbioavailability. For such studies, the compounds can be dissolved invarious vehicles (e.g. PEG 400 solution and CMC suspension) forintravenous and oral dosing in the rats. Following administration,plasma samples are obtained and extracted. The plasma concentrations ofthe starting compound and HNK metabolite are determined by highperformance liquid chromatography/tandem mass spectrometry (LC/MS/MS)methods. Pharmacokinetic analyses are performed based on the plasmaconcentration data.

In some embodiments, pharmacokinetic data are analyzed, and significantlevels of HNK metabolite are observed following oral administration offormula (I) compounds. Without being limited by mechanism, conversion ofexemplary compounds of Formula (I) to the HNK may include one or more ofa physiochemical, metabolic, or enzymatic process.

Therapeutic Administration of Formula (I) Compositions

The ability of compounds of the present disclosure to treat thedisorders described herein can be evaluated using a suitably designedclinical study, such as that summarized below for a depressive disorder.

In this prophetic example, a clinical trial comprises a randomized,double-blind, placebo-controlled, multiple (21-day) dose study in twentyotherwise-healthy male and female patients with moderate-to-severe,major depressive disorder (as defined by the American PsychiatryAssociation Diagnostic and Statistical Manual of Mental Disorders (5thedition) and confirmed by the Mini International NeuropsychiatricInterview) of severity (as assessed by the Montgomery-Asberg DepressionRating Scale).

The patients are randomized into 2 cohorts. Subjects in cohort 1 receivesingle doses of a Formula (I) solid dosage formulation on days 1-21.Subject in cohort 2 are identical to those for cohort 1, except thatthey receive single doses of placebo on days 1-21.

For each cohort, multiple parameters, including pharmacokinetics (PK),safety, and pharmacodynamics (PD) data are evaluated. In addition,cognitive function in Cohorts 1 and 2 is assessed using the CogStatetesting method, which comprises a customizable range of computerizedcognitive tasks able to measure baseline and change in all cognitivedomains. Specialized tasks in CogState can assess attention, memory,executive function, as well as language and social-emotional cognition.

Under the dosing duration of 3 weeks (21 days), there is evidence ofFormula (I) compound-induced changes on PD endpoints that indicate anantidepressant effect. There is also evidence of a rapid onset ofantidepressant effects, in some cases following a single dose. Inaddition, there is evidence of compound-induced changes in cognitivedomain function.

In another prophetic example, comparable results are obtained from asimilarly-designed clinical trial evaluating the efficacy of Formula (I)compounds in treating male and female patients with treatment-resistantdepression (as defined by the American Psychiatry Association Diagnosticand Statistical Manual of Mental Disorders (5th Edition).

Conversion of Formula (I) Compositions

In this prophetic example, exemplary compounds of Formula (I) yield HNKupon administration to a subject, such as a patient in a clinical trial,in one or more steps. For example, in one possible pathway illustratedin the following schematic, exemplary compounds of Formula (I) may yieldHNK in a two-step process, consisting of hydrolysis in Step 1 under acidconditions, such as those in the stomach, and subsequent enzymaticconversion by esterase action.

As a more specific example, a compound of Example 2 may give rise to HNKand lactic acid by the proposed two-step process, as illustrated in thefollowing schematic.

The preceding schematics are for illustration purposes only and notintended to be limited to a particular mechanism or pathway, as otherscenarios are also possible.

While certain embodiments are described herein, it is understood thatthe described embodiments are not intended to limit the scope of thedisclosure as defined by the appended claims. On the contrary, thepresent disclosure is intended to cover alternatives, modifications andequivalents that may be included within the spirit and scope of theinvention as defined by the appended claims. Furthermore, certaindetails in the present disclosure are provided to convey a thoroughunderstanding of the invention defined by the appended claims. However,it will be apparent to those skilled in the art that certain embodimentsmay be practiced without these details. In certain instances, well-knownmethods, procedures, or other specific details have not been describedto avoid unnecessarily obscuring aspects of the invention defined by theappended claims.

What is claimed is:
 1. A method of treating a major depressive disorderor persistent depressive disorder, comprising administering to a patientin need thereof a therapeutically effective amount of a compound, orpharmaceutically acceptable salt thereof, of Formula (I):

wherein: R¹ is —H; or R¹ is —C₁₋₆alkyl, optionally substituted with oneor more members, each independently selected from the group consistingof: -halo, -hydroxy, -alkoxy, -amino and -carboxyl; or R¹ is—C₃₋₈alkenyl or —C₃₋₈alkynyl, each optionally substituted with one ormore members, each independently selected from the group consisting of:-halo, -hydroxy, —C₁₋₄ alkyl, —C₁₋₄alkoxy, and amino; or R¹ is—(CH₂)_(n)aryl, —(CH₂)_(n)heteroaryl, —(CH₂)_(n)cycloalkyl, or—(CH₂)_(n)heterocycloalkyl, each optionally substituted with one or moremembers, each independently selected from the group consisting of:-halo, -hydroxy, —C₁₋₄ alkyl, —C₁₋₄alkoxy, and -amino, wherein n isindependently an integer selected from 0, 1, 2, 3, and 4; or R¹ is—COR², —CONR³R⁴, —CR⁵R⁶NR⁷R⁸, —CHR⁹R¹⁰, or —C(OH)R¹¹R¹², wherein R², R³,R⁴, R⁷ and R⁸ are each independently selected from the group consistingof: —H, —C₁₋₈alkyl, and —C₁₋₈haloalkyl; R⁵ and R⁶ are each independentlyselected from the group consisting of: —H, -halo, —NH₂, —C₁₋₈alkyl,—C₁₋₈haloalkyl, —(CH₂)_(n)CONH₂, —(CH₂)_(n)COOH, —(CH₂)_(n)aryl,—(CH₂)_(n)heteroaryl, —(CH₂)_(n)cycloalkyl, and—(CH₂)_(n)heterocycloalkyl, each optionally substituted with one or moremembers, each independently selected from the group consisting of:-guanidyl, -urea, -halo, -alkyl, -hydroxy, -amino, -alkoxy,-2,3-dihydro-1H-pyrrole-1-carboxamide, —(CH₂)_(n)CONR^(1A)R^(1B),—(CH₂)^(n)NHC(═O)R^(1A), —(CH₂)_(n)NR^(1A)R^(1B), —(CH₂)_(n)ORC,—(CH₂)_(n)SR^(1C) and —(CH₂)_(n)SeR^(1C), wherein n is independently aninteger selected from 0, 1, 2, 3, and 4; each R^(1A) is independentlyselected from the group consisting of: —H —C₁₋₈alkyl, —(CH₂)_(n)CONH₂,and —(CH₂)_(n)heterocycloalkyl, wherein n is independently an integerselected from 0, 1, 2, 3, and 4; each R^(1B) is independently selectedfrom the group consisting of: —H, —C₁₋₈alkyl, and —(CH₂)_(n)CONH₂,wherein n is independently an integer selected from 0, 1, 2, 3, and 4;each R^(1C) is independently selected from the group consisting of: —H—C₁₋₈alkyl, —C₁₋₈haloalkyl, —(CH₂)_(n)CONH₂, —(CH₂)_(n)COOH,—(CH₂)_(n)aryl, —(CH₂)_(n)heteroaryl, —(CH₂)_(n)cycloalkyl, and—(CH₂)_(n)heterocycloalkyl, wherein n is independently an integerselected from 0, 1, 2, 3, and 4; R⁹ and R¹⁰ are each independentlyselected from the group consisting of: —H, —C₁₋₈alkyl, and—C₁₋₈haloalkyl, said alkyl optionally substituted with up to 3 members,each independently selected from the group consisting of: -amino,-hydroxy and -carboxyl; or optionally R⁹ and R¹⁰ taken together with thecarbon to which they are attached form an optionally substituted fivemembered heteroaryl or heterocycloalkyl ring; and R¹¹ and R¹² areindependently selected from the group consisting of: —H, —C₁₋₆alkyl, and—C₁₋₆haloalkyl, said —C₁₋₆alkyl, and —C₁₋₆haloalkyl optionallysubstituted with up to 3 members, each independently selected from thegroup consisting of: —hydroxy and amino.
 2. The method of claim 1,wherein: R¹ is —H; or R¹ is —C₁₋₆alkyl, optionally substituted with oneor more members, each independently selected from the group consistingof: -halo, -hydroxy, -alkoxy, -amino and -carboxyl; or R¹ is—C₃₋₈alkenyl or —C₃₋₈alkynyl, each optionally substituted with one ormore members, each independently selected from the group consisting of:-halo, -hydroxy, —C₁₋₄alkyl, —C₁₋₄alkoxy, and amino; or R¹ is—(CH₂)_(n)aryl, —(CH₂)_(n)heteroaryl, —(CH₂)_(n)cycloalkyl, or—(CH₂)_(n)heterocycloalkyl, each optionally substituted with one or moremembers, each independently selected from the group consisting of:-halo, -hydroxy, —C₁₋₄ alkyl, —C₁₋₄alkoxy, and -amino, wherein n isindependently an integer selected from 0, 1, 2, 3, and 4; or R¹ is—CR⁵R⁶NR⁷R⁸, —CHR⁹R¹⁰, or —C(OH)R¹R¹², wherein R⁷ and R⁸ areindependently selected from the group consisting of: —H, —C₁₋₈alkyl, and—C₁₋₈haloalkyl; R⁵ and R⁶ are each independently selected from the groupconsisting of: —H, -halo, —NH₂, —C₁₋₈alkyl, —C₁₋₈haloalkyl,—(CH₂)_(n)CONH₂, —(CH₂)_(n)COOH, —(CH₂)_(n)aryl, —(CH₂)_(n)heteroaryl,—(CH₂)_(n)cycloalkyl, and —(CH₂)_(n)heterocycloalkyl, each optionallysubstituted with one or more members, each independently selected fromthe group consisting of: -guanidyl, -urea, -halo, -alkyl, -hydroxy,-amino, -alkoxy, -2,3-dihydro-1H-pyrrole-1-carboxamide,—(CH₂)_(n)NR^(1A)R^(1B), —(CH₂)_(n)OR^(1C), —(CH₂)_(n)SR^(1C) and—(CH₂)_(n)SeR^(1C), wherein n is independently an integer selected from0, 1, 2, 3, and 4; each R^(1A) is independently selected from the groupconsisting of: —H —C₁₋₈alkyl, and —(CH₂)_(n)heterocycloalkyl, wherein nis independently an integer selected from 0, 1, 2, 3, and 4; each R^(1B)is independently selected from the group consisting of: —H and—C₁₋₈alkyl, wherein n is independently an integer selected from 0, 1, 2,3, and 4; each R^(1C) is independently selected from the groupconsisting of: —H, —C₁₋₈alkyl, —C₁₋₈haloalkyl, —(CH₂)_(n)aryl,—(CH₂)_(n)heteroaryl, —(CH₂)_(n)cycloalkyl, and—(CH₂)_(n)heterocycloalkyl, wherein n is independently an integerselected from 0, 1, 2, 3, and 4; R⁹ and R¹⁰ are each independentlyselected from the group consisting of: —H, —C₁₋₈alkyl, and—C₁₋₈haloalkyl, said alkyl optionally substituted with up to 3 members,each independently selected from the group consisting of -amino,-hydroxy, and -carboxyl; or optionally R⁹ and R¹⁰ taken together withthe carbon to which they are attached can form an optionally substitutedfive membered heteroaryl or heterocycloalkyl ring; and R¹¹ and R¹² areeach independently selected from the group consisting of: —H,—C₁₋₆alkyl, and —C₁₋₆haloalkyl, said —C₁₋₆alkyl, and —C₁₋₆haloalkyloptionally substituted with up to 3 members, each independently selectedfrom the group consisting of: -hydroxy and -amino.
 3. The method ofclaim 1, wherein: R¹ is —CR⁵R⁶NR⁷R⁸ or —CR⁹R¹⁰, wherein R⁵ and R⁶ areindependently selected from the group consisting of: —H, —F, —Cl, —Br,—NH₂, -methyl, -ethyl, -n-propyl, -isopropyl, -butyl, -pentyl, —NH₂,—C₁₋₈haloalkyl, —(CH₂)_(n)CONH₂, —(CH₂)_(n)COOH, —(CH₂)_(n)aryl,—(CH₂)_(n)benzyl, —(CH₂)_(n)heteroaryl, —(CH₂)indole, —(CH₂)imidazole,—(CH₂)_(n)cycloalkyl, —(CH₂)_(n)heterocycloalkyl, —(CH₂)_(n)pyrrolidine,—(CH₂)furan, and —(CH₂)_(n)thiophene, optionally substituted with up to3 members, each independently selected from the group consisting of:-guanidyl, -urea, -halo, -alkyl, -hydroxy, -amino, -alkoxy,-2,3-dihydro-1H-pyrrole-1-carboxamide, —(CH₂)_(n)NR^(1A)R^(1B),—(CH₂)_(n)OR^(1C), —(CH₂)_(n)SR^(1C) and —(CH₂)_(n)SeR^(1C), wherein nis independently an integer selected from 0, 1, 2, 3, and 4; each R^(1A)is independently selected from the group consisting of: —H, —C₁₋₈alkyl,and —(CH₂)_(n)heterocycloalkyl, wherein n is independently an integerselected from 0, 1, 2, 3, and 4; each R^(1B) is independently selectedfrom the group consisting of: —H and —C₁₋₈alkyl, wherein n isindependently an integer selected from 0, 1, 2, 3, and 4; each R^(1C) isindependently selected from the group consisting of: —H —C₁₋₈alkyl,—C₁₋₈haloalkyl, —(CH₂)_(n)aryl, —(CH₂)_(n)heteroaryl,—(CH₂)_(n)cycloalkyl, and —(CH₂)_(n)heterocycloalkyl, wherein n isindependently an integer selected from 0, 1, 2, 3, and 4; R⁷ and R⁸ are—H; and R⁹ and R¹⁰ are independently selected from the group consistingof: —H, —C₁₋₈alkyl, and —C₁₋₈haloalkyl; or optionally R⁹ and R¹⁰ takentogether with the carbon to which they are attached can form anoptionally substituted five membered heteroaryl or heterocycloalkylring.
 4. The method of claim 1, wherein the therapeutically effectiveamount is an amount sufficient to achieve remission on a depressionsymptoms rating scale.
 5. A method of treating a major depressivedisorder or persistent depressive disorder comprising administering to apatient in need thereof a therapeutically effective amount of a compoundselected from the group consisting of:(1R,5R)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1R,5R)-5-(2-chlorophenyl)-3-methyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1R,5R)-5-(2-chlorophenyl)-3-(1-hydroxyethyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1R,5R)-3-((S)-1-amino-2-methylpropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1R,5R)-3-(aminomethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1R,5R)-5-(2-chlorophenyl)-3-fluorocarbonyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1R,5R)-5-(2-chlorophenyl)-3-((S)-1,5-diaminopentyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1R,5R)-3-((S)-1-aminoethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1R,5R)-5-(2-chlorophenyl)-3-phenyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1R,5R)-3-((1S,2R)-1-amino-2-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1R,5R)-3-((S)-1-amino-3-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1R,5R)-3-((S)-1-amino-2-phenylethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1R,5R)-3-((S)-1-amino-2-(4-hydroxyphenyl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1R,5R)-3-((S)-1-amino-2-(1H-indol-3-yl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1R,5R)-3-((S)-1-amino-2-(1H-imidazol-4-yl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1R,5R)-5-(2-chlorophenyl)-3-(pyrrolidin-2-yl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(S)-3-amino-3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)propanoicacid; (S)-4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)butanoicacid;(S)-4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)butanamide;(S)-3-amino-3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)propanamide;(1R,5R)-3-((S)-1-amino-3-(methylthio)propyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1R,5R)-3-((R)-1-amino-2-mercaptoethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1R,5R)-3-((S)-1-amino-2-hydroxyethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1R,5R)-3-((S)-1-amino-2-methoxyethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;1-((S)-4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)butyl)guanidine;(1R,5R)-5-(2-chlorophenyl)-3-ethyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)-2-hydroxypropanoicacid;2-(((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)methyl)-2-hydroxysuccinicacid;5-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)pentanoicacid;3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)-2,3-dihydroxypropanoicacid;3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)propanoicacid;(1R,5R)-5-(2-chlorophenyl)-3-heptyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1R,5R)-3-(1-amino-2-hydroselenoethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1R,5R)-5-(2-chlorophenyl)-3-(2-(methylamino)ethyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1R,5R)-5-(2-chlorophenyl)-3-(1,2-diaminoethyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1R,5R)-3-(2-amino-1-hydroxyethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1R,5R)-3-(3-aminopropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1R,5R)-3-(4-aminobutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1R,5R)-3-(3-aminopentyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1R,5R)-3-(1-amino-3-hydroxypropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1R,5R)-5-(2-chlorophenyl)-3-(1,4-diaminobutyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)-N-ethylbutanamide;(1R,5R)-5-(2-chlorophenyl)-3-(1,5-diamino-4-hydroxypentyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;1-(4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)butyl)urea;1-(5-amino-5-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)pentyl)urea;1-(5-amino-5-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)pentyl)guanidine;1-(2-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)ethyl)guanidine;(1R,5R)-3-(1-amino-2-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1R,5R)-3-(1-amino-2-(5-hydroxy-1H-indol-3-yl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1R,5R)-3-(1-amino-2-(5-methyl-1H-indol-3-yl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3:1]non-3-en-9-one;(1R,5R)-3-(2-(1H-indol-3-yl)-1-(methylamino)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1R,5R)-5-(2-chlorophenyl)-3-(4-hydroxypyrrolidin-2-yl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1R,5R)-3-(1-amino-2-hydroxy-3-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1R,5R)-5-(2-chlorophenyl)-3-(1-(methylamino)ethyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1R,5R)-3-(2-aminopropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;N-(5-amino-5-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)pentyl)-3-methyl-3,4-dihydro-2H-pyrrole-2-carboxamide;(1R,5R)-3-(1-amino-3-hydroxy-2-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1R,5R)-3-(1-amino-2,2-dimethylpropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1R,5R)-3-(amino(3-amino-4-hydroxyphenyl)methyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1R,5R)-3-(1-amino-2-hydroxy-2-phenylethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1R,5R)-3-(1-amino-2-(4-methoxyphenyl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1 S,5 S)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one; (1S,5S)-5-(2-chlorophenyl)-3-methyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1 S,5S)-5-(2-chlorophenyl)-3-(1-hydroxyethyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1 S,5S)-3-((S)-1-amino-2-methylpropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1 S,5S)-3-(aminomethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1S,5S)-5-(2-chlorophenyl)-3-fluorocarbonyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1 S,5S)-5-(2-chlorophenyl)-3-((S)-1,5-diaminopentyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1S,5S)-3-((S)-1-aminoethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1 S,5S)-5-(2-chlorophenyl)-3-phenyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1S,5 S)-3-((1S,2R)-1-amino-2-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1 S,5S)-3-((S)-1-amino-3-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1 S,5S)-3-((S)-1-amino-2-phenylethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1 S,5S)-3-((S)-1-amino-2-(4-hydroxyphenyl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1 S,5S)-3-((S)-1-amino-2-(1H-indol-3-yl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1S,5S)-3-((S)-1-amino-2-(1H-imidazol-4-yl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1 S,5S)-5-(2-chlorophenyl)-3-(pyrrolidin-2-yl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(S)-3-amino-3-((1 S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)propanoicacid; (S)-4-amino-4-((1 S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)butanoicacid; (S)-4-amino-4-((1 S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)butanamide;(S)-3-amino-3-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)propanamide;(1 S,5S)-3-((S)-1-amino-3-(methylthio)propyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1 S,5S)-3-((R)-1-amino-2-mercaptoethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1 S,5S)-3-((S)-1-amino-2-hydroxyethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1 S,5S)-3-((S)-1-amino-2-methoxyethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;1-((S)-4-amino-4-((1 S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)butyl)guanidine;(1 S,5S)-5-(2-chlorophenyl)-3-ethyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;3-((1 S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)-2-hydroxypropanoicacid; 2-(((1 S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)methyl)-2-hydroxysuccinicacid; 5-((1 S, 5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)pentanoicacid; 3-((1 S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)-2,3-dihydroxypropanoicacid; 3-((1 S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)propanoicacid; (1 S,5S)-5-(2-chlorophenyl)-3-heptyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1 S,5S)-3-(1-amino-2-hydroselenoethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1 S,5S)-5-(2-chlorophenyl)-3-(2-(methylamino)ethyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1 S,5S)-5-(2-chlorophenyl)-3-(1,2-diaminoethyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1S,5S)-3-(2-amino-1-hydroxyethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1 S,5S)-3-(3-aminopropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1S,5S)-3-(4-aminobutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1 S,5S)-3-(3-aminopentyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1S,5S)-3-(1-amino-3-hydroxypropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1 S,5S)-5-(2-chlorophenyl)-3-(1,4-diaminobutyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;4-amino-4-((1 S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)-N-ethylbutanamide;(1 S,5S)-5-(2-chlorophenyl)-3-(1,5-diamino-4-hydroxypentyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;1-(4-amino-4-((1 S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)butyl)urea;1-(5-amino-5-((1 S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)pentyl)urea;1-(5-amino-5-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)pentyl)guanidine;1-(2-((1 S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)ethyl)guanidine;(1S,5S)-3-(1-amino-2-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1S,5S)-3-(1-amino-2-(5-hydroxy-1H-indol-3-yl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1S,5S)-3-(1-amino-2-(5-methyl-1H-indol-3-yl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1S,5S)-3-(2-(1H-indol-3-yl)-1-(methylamino)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1S,5S)-5-(2-chlorophenyl)-3-(4-hydroxypyrrolidin-2-yl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1S,5S)-3-(1-amino-2-hydroxy-3-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1 S,5S)-5-(2-chlorophenyl)-3-(1-(methylamino)ethyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1 S,5S)-3-(2-aminopropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;N-(5-amino-5-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)pentyl)-3-methyl-3,4-dihydro-2H-pyrrole-2-carboxamide;(1 S,5S)-3-(1-amino-3-hydroxy-2-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1 S,5S)-3-(1-amino-2,2-dimethylpropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1 S,5S)-3-(amino(3-amino-4-hydroxyphenyl)methyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1S,5S)-3-(1-amino-2-hydroxy-2-phenylethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1 S,5S)-3-(1-amino-2-(4-methoxyphenyl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;and pharmaceutically acceptable salts thereof.
 6. The method of claim 5,wherein the compound is selected from the group consisting of:(1R,5R)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(S)-3-amino-3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)propanoicacid; (S)-4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)butanoicacid;(S)-4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)butanamide;(S)-3-amino-3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)propanamide;(1R,5R)-3-((S)-1-amino-3-(methylthio)propyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(1R,5R)-3-((R)-1-amino-2-mercaptoethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;1-((S)-4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)butyl)guanidine;3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)-2-hydroxypropanoicacid;2-(((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)methyl)-2-hydroxysuccinicacid;5-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)pentanoicacid;3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)-2,3-dihydroxypropanoicacid;3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)propanoicacid; 4-amino-4-((1, R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)-N-ethylbutanamide;1-(4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)butyl)urea;1-(5-amino-5-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)pentyl)urea;1-(5-amino-5-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)pentyl)guanidine;1-(2-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)ethyl)guanidine;N-(5-amino-5-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)pentyl)-3-methyl-3,4-dihydro-2H-pyrrole-2-carboxamide;and pharmaceutically acceptable salts thereof.
 7. The method of claim 5,wherein the compound is selected from the group consisting of:(1R,5R)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;(S)-3-amino-3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)propanoicacid;(S)-4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)butanoicacid;(S)-4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)butanamide;(S)-3-amino-3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)propanamide;(1R,5R)-3-((S)-1-amino-3-(methylthio)propyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;1-((S)-4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)butyl)guanidine;3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)-2-hydroxypropanoicacid;3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)-2,3-dihydroxypropanoicacid;3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-yl)propanoicacid; and pharmaceutically acceptable salts thereof.
 8. The method ofclaim 5, wherein the therapeutically effective amount is an amountsufficient to achieve remission on a depression symptoms rating scale.